chr12-2486257-T-C

Position:

• chr12-2486257-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.911T>C​(p.Ile304Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000954 in 1,612,986 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: 1.42

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.013324827).
• BP6: Variant 12-2486257-T-C is Benign according to our data. Variant chr12-2486257-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190631.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=1}. Variant chr12-2486257-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000624 (95/152192) while in subpopulation NFE AF= 0.00107 (73/68012). AF 95% confidence interval is 0.000875. There are 0 homozygotes in gnomad4. There are 40 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.911T>C	p.Ile304Thr	missense_variant	6/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.911T>C	p.Ile304Thr	missense_variant	6/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.911T>C	p.Ile304Thr	missense_variant	6/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.911T>C	p.Ile304Thr	missense_variant	6/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1001T>C	p.Ile334Thr	missense_variant	6/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.911T>C	p.Ile304Thr	missense_variant	6/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.911T>C	p.Ile304Thr	missense_variant	6/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1001T>C	p.Ile334Thr	missense_variant	6/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.911T>C	p.Ile304Thr	missense_variant	6/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.911T>C	p.Ile304Thr	missense_variant	6/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.911T>C	p.Ile304Thr	missense_variant	6/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1001T>C	p.Ile334Thr	missense_variant	6/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1001T>C	p.Ile334Thr	missense_variant	6/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1001T>C	p.Ile334Thr	missense_variant	6/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1001T>C	p.Ile334Thr	missense_variant	6/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.911T>C	p.Ile304Thr	missense_variant	6/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.911T>C	p.Ile304Thr	missense_variant	6/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.911T>C	p.Ile304Thr	missense_variant	6/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.911T>C	p.Ile304Thr	missense_variant	6/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.911T>C	p.Ile304Thr	missense_variant	6/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.911T>C	p.Ile304Thr	missense_variant	6/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.911T>C	p.Ile304Thr	missense_variant	6/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.911T>C	p.Ile304Thr	missense_variant	6/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.911T>C	p.Ile304Thr	missense_variant	6/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.911T>C	p.Ile304Thr	missense_variant	6/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.911T>C	p.Ile304Thr	missense_variant	6/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.860T>C	p.Ile287Thr	missense_variant	5/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.911T>C		non_coding_transcript_exon_variant	6/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000500 AC: 124 AN: 248032 Hom.: 0 AF XY: 0.000558 AC XY: 75 AN XY: 134508

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000945

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000988 AC: 1443 AN: 1460794 Hom.: 1 Cov.: 31 AF XY: 0.000943 AC XY: 685 AN XY: 726604

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00119

Gnomad4 OTH exome AF: 0.000845

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000538 AC XY: 40 AN XY: 74418

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000985 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000495 AC: 60

EpiCase AF: 0.00109

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2017	A variant of uncertain significance has been identified in the CACNA1C gene. The I304T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant has previously been observed independently or in conjunction with additional cardiogenetic variants in multiple other unrelated individuals referred for arrhythmia genetic testing at GeneDx. However, segregation data is uninformative. In addition, this variant has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000231571.1, SCV000259358.1, SCV000318927.1, SCV000280059.1; Landrum et al., 2016). The NHLBI Exome Sequencing Project and the Exome Aggregation Consortium (ExAC) report the I304T variant was observed in 10/8,588 alleles from individuals of European background and 58/66,110 alleles from individual of Non-Finnish European background, respectively. This substitution occurs at a position that is not conserved across species, and Threonine is the wild-type amino acid at this position in at least one species. Furthermore, in silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the I304T variant results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given the lack of case data and the rare occurrence in individuals not selected for Mendelian phenotypes, we consider this a variant of uncertain significance. The variant is novel. In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts it to be tolerated. The isoleucine at codon 304 is not conserved across species. The variant was reported online in 30 of 60,304 individuals (including 29 of 36,923 European individuals, 1 of 4949 African-American individuals, and 1 of 5780 Latino Individuals) in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) (as of December 1st, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 16, 2024	Variant summary: CACNA1C c.911T>C (p.Ile304Thr) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0005 in 248032 control chromosomes. The observed variant frequency is approximately 49.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05). c.911T>C has been reported in the literature in individuals affected with Long QT syndrome, arrythmia, and Brugada syndrome (Wemhoner_2015, VanLint_2019, Bora_2023, Novelli_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 37901857, 34999275, 30847666, 25633834). ClinVar contains an entry for this variant (Variation ID: 190631). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CACNA1C: PP2, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 11, 2018	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CACNA1C NM_000719.6 exon 6 p.Ile304Thr (c.911T>C): This variant has not been reported in the literature but is present in 0.1% (11/10290) of Ashkenazi Jewish alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/12-2595423-T-C). This variant is present in ClinVar (Variation ID:190631). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Timothy syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 18, 2024

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.71
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.20	N
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0088	T
MutationAssessor	Benign	-0.14	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.96	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.018, 0.0, 0.0020, 0.066, 0.015, 0.0010, 0.0080, 0.026, 0.061, 0.099, 0.37	.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B
Vest4		0.10
MVP		0.74
MPC		1.3
ClinPred		0.014	T
GERP RS		2.7
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201756421; hg19: chr12-2595423;