rs786205751

Variant names:

• chr12-2584605-A-G
• rs786205751
• NM_000719.7:c.2327A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.2327A>G​(p.Lys776Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,612,026 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: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.51

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 -5 ACMG points.

• 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=0.2536962).
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2417A>G	p.Lys806Arg	missense_variant	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2492A>G	p.Lys831Arg	missense_variant	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2417A>G	p.Lys806Arg	missense_variant	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2417A>G	p.Lys806Arg	missense_variant	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2417A>G	p.Lys806Arg	missense_variant	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2417A>G	p.Lys806Arg	missense_variant	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2402A>G	p.Lys801Arg	missense_variant	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2402A>G	p.Lys801Arg	missense_variant	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2318A>G	p.Lys773Arg	missense_variant	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2327A>G	p.Lys776Arg	missense_variant	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*934A>G		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*934A>G		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248138 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134708

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459822 Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6 AN XY: 726170

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Feb 08, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Long QT syndrome Uncertain:1

Oct 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 776 of the CACNA1C protein (p.Lys776Arg). This variant is present in population databases (rs786205751, gnomAD 0.002%). 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: 190649). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. 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. -

Cardiovascular phenotype Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.K776R variant (also known as c.2327A>G), located in coding exon 16 of the CACNA1C gene, results from an A to G substitution at nucleotide position 2327. The lysine at codon 776 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al.Nature. 2020 May;581(7809):434-443; Whiffin et al.Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration withCACNA1C-related neurodevelopmental disorderis unknown; however, the association withTimothy syndrome or Long QT syndrome without extracardiac findingsis unlikely. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.4	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Benign	0.24	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	0.47	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, 0.97, 0.0080, 0.0040, 0.0, 0.79, 0.91, 0.85, 0.91, 0.68	.;D;D;B;B;B;P;P;P;B;P;P;P;D;P;P;.;P;P;.;P;.;P
Vest4		0.33
MVP		0.89
MPC		0.89
ClinPred		0.29	T
GERP RS		3.6
gMVP		0.66

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: rs786205751; hg19: chr12-2693771;