chr12-2679690-C-T

Variant names:

• chr12-2679690-C-T
• rs371760034
• NM_000719.7:c.5338C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5338C>T​(p.Arg1780Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,612,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.893

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:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 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=0.18304664).
• BP6: Variant 12-2679690-C-T is Benign according to our data. Variant chr12-2679690-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190688.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5572C>T	p.Arg1858Cys	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5305C>T	p.Arg1769Cys	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5503C>T	p.Arg1835Cys	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5482C>T	p.Arg1828Cys	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5461C>T	p.Arg1821Cys	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5428C>T	p.Arg1810Cys	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5428C>T	p.Arg1810Cys	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5428C>T	p.Arg1810Cys	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5428C>T	p.Arg1810Cys	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5422C>T	p.Arg1808Cys	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5413C>T	p.Arg1805Cys	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5398C>T	p.Arg1800Cys	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5395C>T	p.Arg1799Cys	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5395C>T	p.Arg1799Cys	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5395C>T	p.Arg1799Cys	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5389C>T	p.Arg1797Cys	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5380C>T	p.Arg1794Cys	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5362C>T	p.Arg1788Cys	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5362C>T	p.Arg1788Cys	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5356C>T	p.Arg1786Cys	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5338C>T	p.Arg1780Cys	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5329C>T	p.Arg1777Cys	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5305C>T	p.Arg1769Cys	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000452 AC: 11 AN: 243174 Hom.: 0 AF XY: 0.0000227 AC XY: 3 AN XY: 132246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000234

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: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460058 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 726182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000202

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: 0.0000162

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74482

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000654 Hom.: 0

Bravo AF: 0.0000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000496 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Feb 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Nov 15, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190688; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

not specified Benign:1

Dec 12, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.5338C>T (p.Arg1780Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 1612396 control chromosomes, predominantly at a frequency of 0.00017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.5338C>T in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 21, 2025

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.69	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.18	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	-0.047	T
MutationAssessor	Benign	0.34	.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;D;D;D;D;N;D;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T;D;T;.
Sift4G	Uncertain	0.056	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010, 0.0020	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.24
MVP		0.32
MPC		0.26
ClinPred		0.054	T
GERP RS		0.46
gMVP		0.49

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: rs371760034; hg19: chr12-2788856; COSMIC: COSV105227173; COSMIC: COSV105227173;