12-2593232-G-C

Variant names:

• chr12-2593232-G-C
• rs767204844
• NM_000719.7:c.2550G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.2550G>C​(p.Glu850Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,461,374 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: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

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 -2 ACMG points.

• PM1: In a region_of_interest Interaction with STAC2 (size 47) in uniprot entity CAC1C_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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=0.35351548).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2640G>C	p.Glu880Asp	missense_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2715G>C	p.Glu905Asp	missense_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2640G>C	p.Glu880Asp	missense_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2640G>C	p.Glu880Asp	missense_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2640G>C	p.Glu880Asp	missense_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2640G>C	p.Glu880Asp	missense_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2625G>C	p.Glu875Asp	missense_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2625G>C	p.Glu875Asp	missense_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2541G>C	p.Glu847Asp	missense_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2550G>C	p.Glu850Asp	missense_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1157G>C		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1157G>C		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 248522 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134822

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 SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461374 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726918

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: 0.0000697

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Jan 05, 2022

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 850 of the CACNA1C protein (p.Glu850Asp). This variant is present in population databases (rs767204844, gnomAD 0.02%). 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: 570288). 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: "Tolerated"; 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	Benign	-0.0082	T
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.35	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	0.86	D
MutationAssessor	Benign	1.6	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D;D;N;N;D;N;D;D;D;N;D;N;D;D;D;N;D;N;D;D;N;D;D
REVEL	Uncertain	0.63
Sift	Benign	0.079	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	0.20	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, 0.22, 0.043, 0.044, 0.088, 1.0, 1.0, 0.99, 0.91	.;D;B;B;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;D;.;P
Vest4		0.57
MutPred		0.34		.;Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);Gain of catalytic residue at M853 (P = 0.048);
MVP		0.89
MPC		1.4
ClinPred		0.67	D
GERP RS		4.1
gMVP		0.42

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: rs767204844; hg19: chr12-2702398;