12-2567592-G-T

Variant names:

• chr12-2567592-G-T
• NM_000719.7:c.1693G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.1693G>T​(p.Ala565Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.76

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000719.7
• 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, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1783G>T	p.Ala595Ser	missense_variant	Exon 13 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1858G>T	p.Ala620Ser	missense_variant	Exon 14 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1783G>T	p.Ala595Ser	missense_variant	Exon 13 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1783G>T	p.Ala595Ser	missense_variant	Exon 13 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1783G>T	p.Ala595Ser	missense_variant	Exon 13 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1783G>T	p.Ala595Ser	missense_variant	Exon 13 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1768G>T	p.Ala590Ser	missense_variant	Exon 14 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1768G>T	p.Ala590Ser	missense_variant	Exon 14 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1684G>T	p.Ala562Ser	missense_variant	Exon 13 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1693G>T	p.Ala565Ser	missense_variant	Exon 13 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*300G>T		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*300G>T		3_prime_UTR_variant	Exon 11 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jun 22, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Long QT syndrome Uncertain:1

Jul 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 565 of the CACNA1C protein (p.Ala565Ser). This variant is not present in population databases (gnomAD no frequency). 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: 1964117). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.86	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	Benign	0.75	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.15	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	0.39	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, 0.99, 0.88, 0.74, 0.71, 1.0, 0.61, 1.0	.;D;D;P;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.71
MutPred		0.68		.;Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);Gain of catalytic residue at A565 (P = 0.122);
MVP		0.84
MPC		1.7
ClinPred		0.97	D
GERP RS		5.1
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.47		Position offset: 16

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: chr12-2676758;