rs768062636

Variant names:

• chr12-2655171-G-C
• rs768062636
• NM_000719.7:c.4165G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-2655171-G-C
• chr12-2655171-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.4165G>C​(p.Asp1389His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4399G>C	p.Asp1467His	missense_variant	Exon 36 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4132G>C	p.Asp1378His	missense_variant	Exon 33 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4330G>C	p.Asp1444His	missense_variant	Exon 35 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4309G>C	p.Asp1437His	missense_variant	Exon 36 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4231G>C	p.Asp1411His	missense_variant	Exon 34 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4255G>C	p.Asp1419His	missense_variant	Exon 34 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4255G>C	p.Asp1419His	missense_variant	Exon 34 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4255G>C	p.Asp1419His	missense_variant	Exon 34 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4255G>C	p.Asp1419His	missense_variant	Exon 34 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4249G>C	p.Asp1417His	missense_variant	Exon 35 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4240G>C	p.Asp1414His	missense_variant	Exon 35 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4225G>C	p.Asp1409His	missense_variant	Exon 35 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4216G>C	p.Asp1406His	missense_variant	Exon 34 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4207G>C	p.Asp1403His	missense_variant	Exon 34 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4132G>C	p.Asp1378His	missense_variant	Exon 33 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4132G>C	p.Asp1378His	missense_variant	Exon 33 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4126G>C	p.Asp1376His	missense_variant	Exon 33 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4165G>C	p.Asp1389His	missense_variant	Exon 34 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4156G>C	p.Asp1386His	missense_variant	Exon 34 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4132G>C	p.Asp1378His	missense_variant	Exon 33 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249692 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.85
MutPred		0.51		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at T1438 (P = 0.0107);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.93
MPC		2.4
ClinPred		0.99	D
GERP RS		4.0
gMVP		0.96

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: rs768062636; hg19: chr12-2764337;