rs750835733

Variant names:

• chr12-2593252-C-G
• rs750835733
• NM_000719.7:c.2570C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-2593252-C-G
• chr12-2593252-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP3 PP5_Moderate

The NM_000719.7(CACNA1C):​c.2570C>G​(p.Pro857Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P857L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000719.7 (CACNA1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• PP5: Variant 12-2593252-C-G is Pathogenic according to our data. Variant chr12-2593252-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 633643.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2570C>G	p.Pro857Arg	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.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2660C>G	p.Pro887Arg	missense_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2735C>G	p.Pro912Arg	missense_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2660C>G	p.Pro887Arg	missense_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2660C>G	p.Pro887Arg	missense_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2660C>G	p.Pro887Arg	missense_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2660C>G	p.Pro887Arg	missense_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2645C>G	p.Pro882Arg	missense_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2645C>G	p.Pro882Arg	missense_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2561C>G	p.Pro854Arg	missense_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2570C>G	p.Pro857Arg	missense_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1177C>G		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1177C>G		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248512 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726944

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Long qt syndrome 8 Pathogenic:1

Jun 05, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Long QT syndrome Pathogenic:1

Mar 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 857 of the CACNA1C protein (p.Pro857Arg). This variant is present in population databases (rs750835733, gnomAD 0.003%). This missense change has been observed in individuals with long QT syndrome (PMID: 23677916, 32161207; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 633643). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 23677916). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.81	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	1.1	D
MutationAssessor	Pathogenic	3.2	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.6	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	0.86
Sift	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
Sift4G	Uncertain	0.023	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, 0.83, 0.16, 0.96, 1.0, 0.75, 1.0, 0.98	.;D;P;B;D;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.70
MutPred		0.30		.;Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);Gain of solvent accessibility (P = 0.0216);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		4.1
gMVP		0.75

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: rs750835733; hg19: chr12-2702418;