rs369255950

Variant names:

• chr12-2556956-G-A
• rs369255950
• NM_000719.7:c.1487G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2556956-G-A
• chr12-2556956-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_000719.7(CACNA1C):​c.1487G>A​(p.Arg496Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 7.00

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 Likely_benign. Variant got -2 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 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.
• BP6: Variant 12-2556956-G-A is Benign according to our data. Variant chr12-2556956-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190640.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1652G>A	p.Arg551Gln	missense_variant	Exon 12 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1562G>A	p.Arg521Gln	missense_variant	Exon 12 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1562G>A	p.Arg521Gln	missense_variant	Exon 12 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1478G>A	p.Arg493Gln	missense_variant	Exon 11 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*94G>A		non_coding_transcript_exon_variant	Exon 9 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*94G>A		3_prime_UTR_variant	Exon 9 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249244 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135218

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460506 Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26 AN XY: 726644

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74240

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000520 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000496 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R496Q variant of uncertain significance in the CACNA1C gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, R496Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved across species. Furthermore, the majority of in silico algorithms predict R496Q is probably damaging to the protein structure/function. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign. -

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

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 01, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 19, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.6	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.11	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	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.98, 0.86, 0.073, 0.88, 0.94, 1.0, 0.99, 0.59, 0.99, 1.0, 1.0, 0.99, 0.99	.;D;P;B;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.81
MVP		0.96
MPC		1.7
ClinPred		0.21	T
GERP RS		5.0
gMVP		0.87

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: rs369255950; hg19: chr12-2666122;