12-2677841-G-T

Variant names:

• chr12-2677841-G-T
• NM_000719.7:c.5065G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000719.7(CACNA1C):​c.5065G>T​(p.Ala1689Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5299G>T	p.Ala1767Ser	missense_variant	Exon 43 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5032G>T	p.Ala1678Ser	missense_variant	Exon 40 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5230G>T	p.Ala1744Ser	missense_variant	Exon 42 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5209G>T	p.Ala1737Ser	missense_variant	Exon 43 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5188G>T	p.Ala1730Ser	missense_variant	Exon 41 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5155G>T	p.Ala1719Ser	missense_variant	Exon 41 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5155G>T	p.Ala1719Ser	missense_variant	Exon 41 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5155G>T	p.Ala1719Ser	missense_variant	Exon 41 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5155G>T	p.Ala1719Ser	missense_variant	Exon 41 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5149G>T	p.Ala1717Ser	missense_variant	Exon 42 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5140G>T	p.Ala1714Ser	missense_variant	Exon 42 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5125G>T	p.Ala1709Ser	missense_variant	Exon 42 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5122G>T	p.Ala1708Ser	missense_variant	Exon 41 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5122G>T	p.Ala1708Ser	missense_variant	Exon 41 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5122G>T	p.Ala1708Ser	missense_variant	Exon 41 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5116G>T	p.Ala1706Ser	missense_variant	Exon 41 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5107G>T	p.Ala1703Ser	missense_variant	Exon 41 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5089G>T	p.Ala1697Ser	missense_variant	Exon 40 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5089G>T	p.Ala1697Ser	missense_variant	Exon 40 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5083G>T	p.Ala1695Ser	missense_variant	Exon 40 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5065G>T	p.Ala1689Ser	missense_variant	Exon 41 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5056G>T	p.Ala1686Ser	missense_variant	Exon 41 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5032G>T	p.Ala1678Ser	missense_variant	Exon 40 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CACNA1C-related disorder Uncertain:1

Aug 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1C c.5065G>T variant is predicted to result in the amino acid substitution p.Ala1689Ser. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.46	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	0.67	D
MutationAssessor	Uncertain	2.1	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.73	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.18, 0.036, 0.0050, 0.15, 0.14, 0.64, 0.072, 0.38, 0.50, 0.44, 0.54, 0.76, 0.49, 1.0	.;B;B;B;B;B;P;P;B;B;P;P;B;P;P;.;P;P;.;.;.;D;.
Vest4		0.64
MutPred		0.29		.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at A1737 (P = 0.0229);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.82
MPC		0.25
ClinPred		0.67	D
GERP RS		4.5
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2787007;