12-2686202-G-T

Position:

• chr12-2686202-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BS2

The NM_000719.7(CACNA1C):​c.5717G>T​(p.Arg1906Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.42

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 Likely_benign. Variant got -1 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.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6056G>T	p.Arg2019Leu	missense_variant	48/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5930G>T	p.Arg1977Leu	missense_variant	46/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5897G>T	p.Arg1966Leu	missense_variant	45/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5882G>T	p.Arg1961Leu	missense_variant	46/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5861G>T	p.Arg1954Leu	missense_variant	47/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5840G>T	p.Arg1947Leu	missense_variant	45/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5822G>T	p.Arg1941Leu	missense_variant	46/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5822G>T	p.Arg1941Leu	missense_variant	46/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5807G>T	p.Arg1936Leu	missense_variant	45/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5807G>T	p.Arg1936Leu	missense_variant	45/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5807G>T	p.Arg1936Leu	missense_variant	45/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5807G>T	p.Arg1936Leu	missense_variant	45/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5801G>T	p.Arg1934Leu	missense_variant	46/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5792G>T	p.Arg1931Leu	missense_variant	46/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5777G>T	p.Arg1926Leu	missense_variant	46/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5774G>T	p.Arg1925Leu	missense_variant	45/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5774G>T	p.Arg1925Leu	missense_variant	45/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5774G>T	p.Arg1925Leu	missense_variant	45/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5768G>T	p.Arg1923Leu	missense_variant	45/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5759G>T	p.Arg1920Leu	missense_variant	45/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5741G>T	p.Arg1914Leu	missense_variant	44/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5741G>T	p.Arg1914Leu	missense_variant	44/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5735G>T	p.Arg1912Leu	missense_variant	44/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5717G>T	p.Arg1906Leu	missense_variant	45/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5717G>T	p.Arg1906Leu	missense_variant	45/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5708G>T	p.Arg1903Leu	missense_variant	45/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5684G>T	p.Arg1895Leu	missense_variant	44/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249308 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135252

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461600 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727090

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2022

This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 1906 of the CACNA1C protein (p.Arg1906Leu). This variant is present in population databases (rs758166168, gnomAD 0.006%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.040	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0070	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.71, 0.027, 0.89, 0.0, 0.87, 0.80, 0.0030, 0.68, 0.87, 1.0	.;P;B;P;B;P;P;P;B;P;P;P;P;D;P;.;P;P;.;.;.;P;.
Vest4		0.73
MVP		0.73
MPC		0.24
ClinPred		0.94	D
GERP RS		4.9
gMVP		0.76

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: rs758166168; hg19: chr12-2795368;