chr12-2691036-G-A

Variant names:

• chr12-2691036-G-A
• rs776275799
• NM_000719.7:c.6254G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_000719.7(CACNA1C):​c.6254G>A​(p.Gly2085Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,451,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.64

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 -7 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=0.10508454).
• BP6: Variant 12-2691036-G-A is Benign according to our data. Variant chr12-2691036-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 527009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6593G>A	p.Gly2198Asp	missense_variant	Exon 50 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6467G>A	p.Gly2156Asp	missense_variant	Exon 48 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6434G>A	p.Gly2145Asp	missense_variant	Exon 47 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6419G>A	p.Gly2140Asp	missense_variant	Exon 48 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6398G>A	p.Gly2133Asp	missense_variant	Exon 49 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6377G>A	p.Gly2126Asp	missense_variant	Exon 47 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6359G>A	p.Gly2120Asp	missense_variant	Exon 48 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6359G>A	p.Gly2120Asp	missense_variant	Exon 48 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6344G>A	p.Gly2115Asp	missense_variant	Exon 47 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6344G>A	p.Gly2115Asp	missense_variant	Exon 47 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6344G>A	p.Gly2115Asp	missense_variant	Exon 47 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6344G>A	p.Gly2115Asp	missense_variant	Exon 47 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6338G>A	p.Gly2113Asp	missense_variant	Exon 48 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6329G>A	p.Gly2110Asp	missense_variant	Exon 48 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6314G>A	p.Gly2105Asp	missense_variant	Exon 48 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6311G>A	p.Gly2104Asp	missense_variant	Exon 47 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6311G>A	p.Gly2104Asp	missense_variant	Exon 47 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6311G>A	p.Gly2104Asp	missense_variant	Exon 47 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6305G>A	p.Gly2102Asp	missense_variant	Exon 47 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6296G>A	p.Gly2099Asp	missense_variant	Exon 47 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6278G>A	p.Gly2093Asp	missense_variant	Exon 46 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6278G>A	p.Gly2093Asp	missense_variant	Exon 46 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6272G>A	p.Gly2091Asp	missense_variant	Exon 46 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6254G>A	p.Gly2085Asp	missense_variant	Exon 47 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6245G>A	p.Gly2082Asp	missense_variant	Exon 47 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6221G>A	p.Gly2074Asp	missense_variant	Exon 46 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152182 Hom.: 0 Cov.: 33 FAILED QC

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: 0.00

GnomAD3 exomes AF: 0.0000133 AC: 3 AN: 225142 Hom.: 0 AF XY: 0.00000815 AC XY: 1 AN XY: 122750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000184

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: 0.00000413 AC: 6 AN: 1451220 Hom.: 0 Cov.: 31 AF XY: 0.00000416 AC XY: 3 AN XY: 720984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74340

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: 0.00

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000829 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.061
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.56	D
M_CAP	Benign	0.018	T
MetaRNN	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
MetaSVM	Benign	-0.94	T
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.058
Sift	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.040	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.034, 0.068, 0.23, 0.0020, 0.16, 0.0060, 0.35, 0.43, 0.73	.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.18
MVP		0.55
MPC		0.41
ClinPred		0.57	D
GERP RS		4.5
gMVP		0.66

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: rs776275799; hg19: chr12-2800202;