rs776242172

Variant names:

• chr12-2512975-C-A
• rs776242172
• NM_000719.7:c.1381C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2512975-C-A
• chr12-2512975-C-G
• chr12-2512975-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM5 PP2 BS2

The NM_000719.7(CACNA1C):​c.1381C>A​(p.Pro461Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 1,450,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P461H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

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 1 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-2512976-C-A is described in Lovd as [Likely_pathogenic].
• 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.
• BS2: High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1471C>A	p.Pro491Thr	missense_variant	Exon 9 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1372C>A	p.Pro458Thr	missense_variant	Exon 9 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1381C>A	p.Pro461Thr	missense_variant	Exon 9 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19589C>A		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000897 AC: 13 AN: 1450002 Hom.: 0 Cov.: 31 AF XY: 0.00000694 AC XY: 5 AN XY: 719986

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000108

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Oct 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline with threonine at codon 461 of the CACNA1C protein (p.Pro461Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs776242172, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 456945). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.64	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	0.70	D
MutationAssessor	Benign	1.4	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.24	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	0.17	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, 0.028, 0.85, 0.61, 0.11	.;D;.;B;P;P;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.73
MutPred		0.27		Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);Gain of phosphorylation at P461 (P = 0.0041);
MVP		0.89
MPC		2.1
ClinPred		0.95	D
GERP RS		4.4
gMVP		0.93

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: rs776242172; hg19: chr12-2622141;