chr12-2556954-C-A

Position:

• chr12-2556954-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.1485C>A​(p.His495Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,612,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.22

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 -8 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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=0.13600987).
• BP6: Variant 12-2556954-C-A is Benign according to our data. Variant chr12-2556954-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190639.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000223 (34/152184) while in subpopulation AFR AF= 0.000821 (34/41426). AF 95% confidence interval is 0.000603. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1485C>A	p.His495Gln	missense_variant	11/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1485C>A	p.His495Gln	missense_variant	11/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1485C>A	p.His495Gln	missense_variant	11/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1485C>A	p.His495Gln	missense_variant	11/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1575C>A	p.His525Gln	missense_variant	11/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1485C>A	p.His495Gln	missense_variant	11/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1485C>A	p.His495Gln	missense_variant	11/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1650C>A	p.His550Gln	missense_variant	12/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1485C>A	p.His495Gln	missense_variant	11/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1485C>A	p.His495Gln	missense_variant	11/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1485C>A	p.His495Gln	missense_variant	11/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1575C>A	p.His525Gln	missense_variant	11/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1575C>A	p.His525Gln	missense_variant	11/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1575C>A	p.His525Gln	missense_variant	11/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1575C>A	p.His525Gln	missense_variant	11/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1485C>A	p.His495Gln	missense_variant	11/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1560C>A	p.His520Gln	missense_variant	12/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1485C>A	p.His495Gln	missense_variant	11/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1560C>A	p.His520Gln	missense_variant	12/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1485C>A	p.His495Gln	missense_variant	11/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1485C>A	p.His495Gln	missense_variant	11/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1485C>A	p.His495Gln	missense_variant	11/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1485C>A	p.His495Gln	missense_variant	11/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1485C>A	p.His495Gln	missense_variant	11/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1476C>A	p.His492Gln	missense_variant	11/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1485C>A	p.His495Gln	missense_variant	11/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*92C>A		non_coding_transcript_exon_variant	9/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*92C>A		3_prime_UTR_variant	9/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000281 AC: 7 AN: 249262 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135228

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1460466 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726640

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74340

Gnomad4 AFR AF: 0.000821

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.000260 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Wolff-Parkinson-White pattern Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

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

Fulgent Genetics, Fulgent Genetics

Jan 03, 2024

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2020

Has not been previously published as pathogenic or benign to our knowledge; Identified in conjunction with additional variants in individuals referred for cardiac genetic testing at GeneDx; segregation data are limited at this time; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190639; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32233023) -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

This alteration is classified as 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	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	20
DANN	Benign	0.70
DEOGEN2	Benign	0.0094	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.85	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.38	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.60	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	0.39	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.59, 0.019, 0.0050, 0.0030, 0.23, 0.57, 0.71, 0.69, 0.99, 0.63	.;P;B;B;B;B;P;P;P;B;P;P;P;P;D;P;.;P;P;.;.;.;P
Vest4		0.47
MutPred		0.42		.;Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);Gain of catalytic residue at R492 (P = 0.015);
MVP		0.96
MPC		1.1
ClinPred		0.022	T
GERP RS		1.6
gMVP		0.72

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: rs373335068; hg19: chr12-2666120;