12-2691189-G-A

Position:

• chr12-2691189-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The ENST00000399655.6(CACNA1C):​c.6407G>A​(p.Ser2136Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S2136S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C ENST00000399655.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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]

CACNA1C-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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=0.22585323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6746G>A	p.Ser2249Asn	missense_variant	50/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6620G>A	p.Ser2207Asn	missense_variant	48/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6587G>A	p.Ser2196Asn	missense_variant	47/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6572G>A	p.Ser2191Asn	missense_variant	48/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6551G>A	p.Ser2184Asn	missense_variant	49/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6530G>A	p.Ser2177Asn	missense_variant	47/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6512G>A	p.Ser2171Asn	missense_variant	48/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6512G>A	p.Ser2171Asn	missense_variant	48/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6497G>A	p.Ser2166Asn	missense_variant	47/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6497G>A	p.Ser2166Asn	missense_variant	47/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6497G>A	p.Ser2166Asn	missense_variant	47/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6497G>A	p.Ser2166Asn	missense_variant	47/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6491G>A	p.Ser2164Asn	missense_variant	48/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6482G>A	p.Ser2161Asn	missense_variant	48/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6467G>A	p.Ser2156Asn	missense_variant	48/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6464G>A	p.Ser2155Asn	missense_variant	47/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6464G>A	p.Ser2155Asn	missense_variant	47/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6464G>A	p.Ser2155Asn	missense_variant	47/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6458G>A	p.Ser2153Asn	missense_variant	47/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6449G>A	p.Ser2150Asn	missense_variant	47/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6431G>A	p.Ser2144Asn	missense_variant	46/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6431G>A	p.Ser2144Asn	missense_variant	46/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6425G>A	p.Ser2142Asn	missense_variant	46/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6407G>A	p.Ser2136Asn	missense_variant	47/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6407G>A	p.Ser2136Asn	missense_variant	47/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6398G>A	p.Ser2133Asn	missense_variant	47/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6374G>A	p.Ser2125Asn	missense_variant	46/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1408540 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 694978

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Apr 11, 2017

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1C-related disease. This sequence change replaces serine with asparagine at codon 2136 of the CACNA1C protein (p.Ser2136Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.0070, 0.33, 0.92, 0.23, 0.99, 0.12, 0.068, 0.37, 0.99, 0.12, 0.52, 0.55, 0.019	.;B;B;P;B;D;B;B;B;B;B;D;B;B;P;.;P;B;.;.;.;B;.
Vest4		0.22
MVP		0.62
MPC		0.19
ClinPred		0.81	D
GERP RS		4.5
gMVP		0.50

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: rs1556337119; hg19: chr12-2800355;