rs373124557

Positions:

• chr12-2610661-G-A
• chr12-2610661-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.3679G>A​(p.Val1227Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,084 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).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 1.55

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 -3 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 57) in uniprot entity CAC1C_HUMAN there are 4 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=0.17503154).
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3679G>A	p.Val1227Ile	missense_variant	28/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3679G>A	p.Val1227Ile	missense_variant	28/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3679G>A	p.Val1227Ile	missense_variant	28/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3829G>A	p.Val1277Ile	missense_variant	29/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3679G>A	p.Val1227Ile	missense_variant	28/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3679G>A	p.Val1227Ile	missense_variant	28/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3844G>A	p.Val1282Ile	missense_variant	29/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3739G>A	p.Val1247Ile	missense_variant	29/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3679G>A	p.Val1227Ile	missense_variant	28/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3679G>A	p.Val1227Ile	missense_variant	28/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3769G>A	p.Val1257Ile	missense_variant	28/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3769G>A	p.Val1257Ile	missense_variant	28/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3769G>A	p.Val1257Ile	missense_variant	28/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3769G>A	p.Val1257Ile	missense_variant	28/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3679G>A	p.Val1227Ile	missense_variant	28/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3754G>A	p.Val1252Ile	missense_variant	29/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3739G>A	p.Val1247Ile	missense_variant	29/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3754G>A	p.Val1252Ile	missense_variant	29/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3679G>A	p.Val1227Ile	missense_variant	28/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3679G>A	p.Val1227Ile	missense_variant	28/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3679G>A	p.Val1227Ile	missense_variant	28/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3679G>A	p.Val1227Ile	missense_variant	28/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3679G>A	p.Val1227Ile	missense_variant	28/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3670G>A	p.Val1224Ile	missense_variant	28/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3679G>A	p.Val1227Ile	missense_variant	28/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2286G>A		non_coding_transcript_exon_variant	26/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2286G>A		3_prime_UTR_variant	26/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250764 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461886 Hom.: 1 Cov.: 31 AF XY: 0.0000413 AC XY: 30 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74364

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 24, 2023	The CACNA1C c.3679G>A; p.Val1227Ile variant (rs373124557), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 234984). This variant is found in the general population with an overall allele frequency of 0.0035% (10/282176 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.283). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 07, 2015	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Mar 18, 2012

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. Based on the data reviewed we consider this a variant of uncertain significance. This is a novel variant. It is not reported in dbSNP as a benign polymorphism nor is it reported in published literature in association with disease. This is a conservative amino acid change with a nonpolar Valine replaced by a nonpolar Leucine. Valine is not conserved at this position across species and there are no reported disease associated variants at nearby codons (Google, Gene Connection for the Heart Database, Mutadatabase). In silico analysis (PolyPhen) predicts the amino acid change to be benign. The reporting lab did not find this variant in 600 presumably healthy controls consisting of both Caucasian and African American ancestry. -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 03, 2021

- -

Short QT Syndrome 4 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Jul 24, 2015

- -

Timothy syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Dec 01, 2017

The observed variant c.3679G>A (p.V1227I) is not reported in 1000 Genomes and has minor allele frequency of 0.00002479 in ExAC database. The in silico prediction of the variant is benign by MutationTaster2 and tolerated by SIFT. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

ClinVar contains an entry for this variant (Variation ID: 234984). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (rs373124557, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1227 of the CACNA1C protein (p.Val1227Ile). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

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	-0.081	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.026
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.18	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	Uncertain	0.34	D
MutationAssessor	Benign	0.81	.;.;.;.;.;.;.;.;.;.;.;L;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.75	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	0.25	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	0.51	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0050, 0.0, 0.032, 0.026, 0.011, 0.012, 0.046, 0.027, 0.014, 0.036, 0.0060, 0.023	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.22
MVP		0.60
MPC		0.87
ClinPred		0.064	T
GERP RS		3.1
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs373124557; hg19: chr12-2719827; COSMIC: COSV59724689; COSMIC: COSV59724689;