rs1219744448

Variant names:

• chr12-2584594-G-T
• rs1219744448
• NM_000719.7:c.2316G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E772K) has been classified 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39954168).

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248632 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111332

Other (OTH) AF: 0.00 AC: 0 AN: 60342

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

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 772 of the CACNA1C protein (p.Glu772Asp). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 526943). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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. -

Cardiovascular phenotype Uncertain:1

Nov 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Pathogenic	0.63
CardioboostArm	Benign	0.0056
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;.;.;.
PhyloP100		3.2
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
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs1219744448; hg19: chr12-2693760;