12-2664961-A-G

Variant names:

• chr12-2664961-A-G
• rs781315664
• NM_000719.7:c.4369A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.4369A>G​(p.Ile1457Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,850 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: 0.0000082 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.83

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_benign. Variant got -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28177345).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4603A>G	p.Ile1535Val	missense_variant	Exon 37 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4336A>G	p.Ile1446Val	missense_variant	Exon 34 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4534A>G	p.Ile1512Val	missense_variant	Exon 36 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4513A>G	p.Ile1505Val	missense_variant	Exon 37 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4435A>G	p.Ile1479Val	missense_variant	Exon 35 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4459A>G	p.Ile1487Val	missense_variant	Exon 35 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4459A>G	p.Ile1487Val	missense_variant	Exon 35 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4459A>G	p.Ile1487Val	missense_variant	Exon 35 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4459A>G	p.Ile1487Val	missense_variant	Exon 35 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4453A>G	p.Ile1485Val	missense_variant	Exon 36 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4444A>G	p.Ile1482Val	missense_variant	Exon 36 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4429A>G	p.Ile1477Val	missense_variant	Exon 36 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4420A>G	p.Ile1474Val	missense_variant	Exon 35 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4411A>G	p.Ile1471Val	missense_variant	Exon 35 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4336A>G	p.Ile1446Val	missense_variant	Exon 34 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4336A>G	p.Ile1446Val	missense_variant	Exon 34 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4330A>G	p.Ile1444Val	missense_variant	Exon 34 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4369A>G	p.Ile1457Val	missense_variant	Exon 35 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4360A>G	p.Ile1454Val	missense_variant	Exon 35 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4336A>G	p.Ile1446Val	missense_variant	Exon 34 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250650 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135680

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461850 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Nov 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1457 of the CACNA1C protein (p.Ile1457Val). This variant is present in population databases (rs781315664, gnomAD 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: 950244). 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 80%. 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	Uncertain	0.054	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.086
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.28	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	1.0	D
MutationAssessor	Benign	0.41	.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.75	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.42
Sift	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.65	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.14, 0.086, 0.012, 0.0070, 0.072, 0.0020, 0.88, 0.0060	.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.18
MutPred		0.42		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at I1505 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.66
MPC		1.2
ClinPred		0.35	T
GERP RS		4.4
gMVP		0.71

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: rs781315664; hg19: chr12-2774127;