chr12-2686216-G-C

Variant names:

• chr12-2686216-G-C
• rs374528680
• NM_000719.7:c.5731G>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4 BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.5731G>C​(p.Gly1911Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,618 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (1 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 5.10

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.27162609).
• BP6: Variant 12-2686216-G-C is Benign according to our data. Variant chr12-2686216-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191427.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000046 (7/152244) while in subpopulation EAS AF= 0.00115 (6/5198). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6070G>C	p.Gly2024Arg	missense_variant	Exon 48 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5944G>C	p.Gly1982Arg	missense_variant	Exon 46 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5911G>C	p.Gly1971Arg	missense_variant	Exon 45 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5896G>C	p.Gly1966Arg	missense_variant	Exon 46 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5875G>C	p.Gly1959Arg	missense_variant	Exon 47 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5854G>C	p.Gly1952Arg	missense_variant	Exon 45 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5836G>C	p.Gly1946Arg	missense_variant	Exon 46 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5836G>C	p.Gly1946Arg	missense_variant	Exon 46 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5821G>C	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5821G>C	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5821G>C	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5821G>C	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5815G>C	p.Gly1939Arg	missense_variant	Exon 46 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5806G>C	p.Gly1936Arg	missense_variant	Exon 46 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5791G>C	p.Gly1931Arg	missense_variant	Exon 46 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5788G>C	p.Gly1930Arg	missense_variant	Exon 45 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5788G>C	p.Gly1930Arg	missense_variant	Exon 45 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5788G>C	p.Gly1930Arg	missense_variant	Exon 45 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5782G>C	p.Gly1928Arg	missense_variant	Exon 45 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5773G>C	p.Gly1925Arg	missense_variant	Exon 45 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5755G>C	p.Gly1919Arg	missense_variant	Exon 44 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5755G>C	p.Gly1919Arg	missense_variant	Exon 44 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5749G>C	p.Gly1917Arg	missense_variant	Exon 44 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5731G>C	p.Gly1911Arg	missense_variant	Exon 45 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5722G>C	p.Gly1908Arg	missense_variant	Exon 45 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5698G>C	p.Gly1900Arg	missense_variant	Exon 44 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152244 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249308 Hom.: 1 AF XY: 0.0000591 AC XY: 8 AN XY: 135252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000556

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461374 Hom.: 1 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 726982

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000978

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74380

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00115

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.0000827 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 05, 2019	- -

Timothy syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Sep 04, 2023	This sequence change in CACNA1C is predicted to replace glycine with arginine at codon 1911, p.(Gly1911Arg). The glycine residue is moderately conserved (100 vertebrates, UCSC), and is located in the cytoplasmic region. There is a large physicochemical difference between glycine and arginine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (11/19,536 alleles) in the East Asian population. This variant has been reported in multiple probands with cardiac phenotypes (PMID: 25184293, 26230511, 23861362). An in vitro functional study using Cav1.2 channel vectors expressed in HEK293T cells showed increased calcium ion production during cardiac action potential suggesting that this variant impacts protein function however limited controls were included in the assay (PMID: 25184293). Computational evidence is uninformative for the missense substitution (REVEL = 0.629). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 29, 2019

Variant summary: CACNA1C c.5731G>C (p.Gly1911Arg) results in a non-conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249708 control chromosomes, predominantly at a frequency of 0.00056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 56 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5731G>C, has been reported in the literature in individuals affected with Brugada Syndrome, long QT syndrome or sudden unexplained infant death (Allegue_2015, Hennessey_2014). However, one publication, Hennessey_2014, suggests the variant is inherited from the asymptomatic father, although his DNA was not available for analysis. In electrophysiological analyses, the variant was observed to cause a gain of function of CaV1.2 suggesting increased susceptibility for arrhythmias in certain clinical settings (Hennessey_2014). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Feb 11, 2018

- -

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

Sep 20, 2021

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2025

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 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	-0.41	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.27	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	-0.85	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.63
Sift	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030, 0.40, 0.25, 0.81, 0.77, 0.90, 0.015, 0.0010, 0.92, 0.57, 0.95, 0.0	.;B;B;B;P;P;P;P;B;B;P;P;P;P;P;.;P;P;.;.;.;B;.
Vest4		0.60
MVP		0.42
MPC		0.31
ClinPred		0.069	T
GERP RS		4.8
gMVP		0.45

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: rs374528680; hg19: chr12-2795382;