chr12-2115376-G-A

Position:

• chr12-2115376-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.202G>A​(p.Ala68Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,606,346 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 0.00013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 4.69

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]

CACNA1C (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 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=0.13323656).
• BP6: Variant 12-2115376-G-A is Benign according to our data. Variant chr12-2115376-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190709.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, Benign=1}.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.202G>A	p.Ala68Thr	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.202G>A	p.Ala68Thr	missense_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.202G>A	p.Ala68Thr	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.202G>A	p.Ala68Thr	missense_variant	2/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.292G>A	p.Ala98Thr	missense_variant	2/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.202G>A	p.Ala68Thr	missense_variant	2/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.202G>A	p.Ala68Thr	missense_variant	2/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.292G>A	p.Ala98Thr	missense_variant	2/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.202G>A	p.Ala68Thr	missense_variant	2/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.202G>A	p.Ala68Thr	missense_variant	2/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.202G>A	p.Ala68Thr	missense_variant	2/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.292G>A	p.Ala98Thr	missense_variant	2/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.292G>A	p.Ala98Thr	missense_variant	2/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.292G>A	p.Ala98Thr	missense_variant	2/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.292G>A	p.Ala98Thr	missense_variant	2/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.202G>A	p.Ala68Thr	missense_variant	2/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.202G>A	p.Ala68Thr	missense_variant	2/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.202G>A	p.Ala68Thr	missense_variant	2/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.202G>A	p.Ala68Thr	missense_variant	2/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.202G>A	p.Ala68Thr	missense_variant	2/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.202G>A	p.Ala68Thr	missense_variant	2/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.202G>A	p.Ala68Thr	missense_variant	2/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.202G>A	p.Ala68Thr	missense_variant	2/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.202G>A	p.Ala68Thr	missense_variant	2/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.202G>A	p.Ala68Thr	missense_variant	2/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.202G>A	p.Ala68Thr	missense_variant	2/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.151G>A	p.Ala51Thr	missense_variant	1/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.202G>A		non_coding_transcript_exon_variant	2/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000149 AC: 35 AN: 234160 Hom.: 0 AF XY: 0.000164 AC XY: 21 AN XY: 128192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000339

Gnomad FIN exome AF: 0.000105

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 206 AN: 1454098 Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 104 AN XY: 723082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000352

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.000174

Gnomad4 OTH exome AF: 0.0000499

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152248 Hom.: 0 Cov.: 34 AF XY: 0.000134 AC XY: 10 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000292 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in association with LQTS, arrhythmia, primary electric disease (PED), and HCM in published literature; at least one patient harbored additional cardiogenetic variants (PMID: 28341588, 23631430, 27231019, 31293105); This variant is associated with the following publications: (PMID: 23631430, 27231019, 31737537, 31293105, 35882527, 28341588) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 06, 2017

Variant summary: The CACNA1C c.202G>A (p.Ala68Thr) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured here due to low reliability index and p-value, respectively). This variant was found in 41/261782 control chromosomes at a frequency of 0.0001566, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000309 (37/119594). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for casualty. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as likely benign. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

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	-0.23	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Benign	0.30
DEOGEN2	Benign	0.0046	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	-0.69	.;.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.8	D;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	0.28
Sift	Benign	0.090	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.054, 0.15, 0.068, 0.24, 0.20, 0.067	.;.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;.
Vest4		0.22, 0.21, 0.26, 0.22, 0.24, 0.18, 0.22, 0.24, 0.25, 0.21, 0.19, 0.21, 0.24, 0.25, 0.22, 0.17, 0.22, 0.20, 0.23, 0.27, 0.21, 0.19
MVP		0.90
MPC		1.0
ClinPred		0.080	T
GERP RS		5.6
gMVP		0.76

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: rs752000790; hg19: chr12-2224542; COSMIC: COSV59707966;