12-2607121-G-C

Position:

• chr12-2607121-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000719.7(CACNA1C):​c.3347G>C​(p.Gly1116Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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-AS3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Dihydropyridine binding (size 89) in uniprot entity CAC1C_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3497G>C	p.Gly1166Ala	missense_variant	27/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3347G>C	p.Gly1116Ala	missense_variant	26/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3512G>C	p.Gly1171Ala	missense_variant	27/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3407G>C	p.Gly1136Ala	missense_variant	27/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3347G>C	p.Gly1116Ala	missense_variant	26/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3347G>C	p.Gly1116Ala	missense_variant	26/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3437G>C	p.Gly1146Ala	missense_variant	26/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3437G>C	p.Gly1146Ala	missense_variant	26/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3437G>C	p.Gly1146Ala	missense_variant	26/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3437G>C	p.Gly1146Ala	missense_variant	26/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3422G>C	p.Gly1141Ala	missense_variant	27/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3407G>C	p.Gly1136Ala	missense_variant	27/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3422G>C	p.Gly1141Ala	missense_variant	27/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3347G>C	p.Gly1116Ala	missense_variant	26/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3347G>C	p.Gly1116Ala	missense_variant	26/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3338G>C	p.Gly1113Ala	missense_variant	26/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3347G>C	p.Gly1116Ala	missense_variant	26/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1954G>C		non_coding_transcript_exon_variant	24/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1954G>C		3_prime_UTR_variant	24/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459918 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726028

Gnomad4 AFR exome AF: 0.0000299

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Sep 01, 2021

This sequence change replaces glycine with alanine at codon 1116 of the CACNA1C protein (p.Gly1116Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). 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: 238173). 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: "Probably Damaging"; 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.9	.;.;.;.;.;.;.;.;.;.;.;H;H;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.85
MutPred		0.72		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at W1137 (P = 0);Gain of catalytic residue at W1137 (P = 0);.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		4.0
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854141; hg19: chr12-2716287;