rs1219744448

Positions:

• chr12-2584594-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.2316G>T​(p.Glu772Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.23

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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=0.39954168).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2316G>T	p.Glu772Asp	missense_variant	16/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2316G>T	p.Glu772Asp	missense_variant	16/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2316G>T	p.Glu772Asp	missense_variant	16/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2406G>T	p.Glu802Asp	missense_variant	16/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2316G>T	p.Glu772Asp	missense_variant	16/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2316G>T	p.Glu772Asp	missense_variant	16/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2481G>T	p.Glu827Asp	missense_variant	17/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2316G>T	p.Glu772Asp	missense_variant	16/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2316G>T	p.Glu772Asp	missense_variant	16/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2316G>T	p.Glu772Asp	missense_variant	16/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2406G>T	p.Glu802Asp	missense_variant	16/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2406G>T	p.Glu802Asp	missense_variant	16/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2406G>T	p.Glu802Asp	missense_variant	16/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2406G>T	p.Glu802Asp	missense_variant	16/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2316G>T	p.Glu772Asp	missense_variant	16/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2391G>T	p.Glu797Asp	missense_variant	17/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2316G>T	p.Glu772Asp	missense_variant	16/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2391G>T	p.Glu797Asp	missense_variant	17/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2316G>T	p.Glu772Asp	missense_variant	16/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2316G>T	p.Glu772Asp	missense_variant	16/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2316G>T	p.Glu772Asp	missense_variant	16/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2316G>T	p.Glu772Asp	missense_variant	16/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2316G>T	p.Glu772Asp	missense_variant	16/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2307G>T	p.Glu769Asp	missense_variant	16/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2316G>T	p.Glu772Asp	missense_variant	16/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*923G>T		non_coding_transcript_exon_variant	14/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*923G>T		3_prime_UTR_variant	14/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248632 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134968

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460874 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726718

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 772 of the CACNA1C protein (p.Glu772Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 16, 2023

The p.E772D variant (also known as c.2316G>T), located in coding exon 16 of the CACNA1C gene, results from a G to T substitution at nucleotide position 2316. The glutamic acid at codon 772 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.032	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.4	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.072	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	0.092	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, 0.97, 0.94, 0.93, 0.036, 1.0, 0.17, 0.98, 0.99	.;D;D;P;P;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.44
MutPred		0.33		.;Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);Loss of ubiquitination at K776 (P = 0.0896);
MVP		0.89
MPC		1.8
ClinPred		0.90	D
GERP RS		3.7
gMVP		0.84

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: rs1219744448; hg19: chr12-2693760;