rs776318939

Variant names:

• chr12-2608545-G-A
• rs776318939
• NM_000719.7:c.3391G>A

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.3391G>A​(p.Asp1131Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,138 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.70

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 region_of_interest Dihydropyridine binding (size 89) in uniprot entity CAC1C_HUMAN there are 6 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 12-2608545-G-A is Benign according to our data. Variant chr12-2608545-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3541G>A	p.Asp1181Asn	missense_variant	Exon 28 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3556G>A	p.Asp1186Asn	missense_variant	Exon 28 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3451G>A	p.Asp1151Asn	missense_variant	Exon 28 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3466G>A	p.Asp1156Asn	missense_variant	Exon 28 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3451G>A	p.Asp1151Asn	missense_variant	Exon 28 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3466G>A	p.Asp1156Asn	missense_variant	Exon 28 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3382G>A	p.Asp1128Asn	missense_variant	Exon 27 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1998G>A		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1998G>A		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249332 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134772

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000233

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: 0.00000548 AC: 8 AN: 1460912 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000179

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: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

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: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ventricular tachycardia Uncertain:1

Mar 04, 2019

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Oct 06, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	-0.091	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.49	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	0.79	D
MutationAssessor	Benign	0.89	.;.;.;.;.;.;.;.;.;.;.;L;L;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.91	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	0.57
Sift	Benign	0.43	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	0.66	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		1.0, 1.0, 0.33, 0.0030, 0.15, 0.088, 1.0, 0.91	.;D;D;B;B;B;D;D;D;B;D;D;D;P;D;D;.;D;D;.;.;.;D;.
Vest4		0.82
MutPred		0.54		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at I1155 (P = 0.0049);Gain of catalytic residue at I1155 (P = 0.0049);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.79
MPC		1.1
ClinPred		0.29	T
GERP RS		4.7
gMVP		0.95

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: rs776318939; hg19: chr12-2717711;