rs727503835

Variant names:

• chr12-2664914-C-T
• rs727503835
• NM_000719.7:c.4322C>T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_000719.7(CACNA1C):​c.4322C>T​(p.Thr1441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,832 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.13

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 Benign. Variant got -7 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=0.021968812).
• BS2: High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4556C>T	p.Thr1519Met	missense_variant	Exon 37 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4289C>T	p.Thr1430Met	missense_variant	Exon 34 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4487C>T	p.Thr1496Met	missense_variant	Exon 36 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4466C>T	p.Thr1489Met	missense_variant	Exon 37 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4388C>T	p.Thr1463Met	missense_variant	Exon 35 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4412C>T	p.Thr1471Met	missense_variant	Exon 35 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4412C>T	p.Thr1471Met	missense_variant	Exon 35 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4412C>T	p.Thr1471Met	missense_variant	Exon 35 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4412C>T	p.Thr1471Met	missense_variant	Exon 35 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4406C>T	p.Thr1469Met	missense_variant	Exon 36 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4397C>T	p.Thr1466Met	missense_variant	Exon 36 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4382C>T	p.Thr1461Met	missense_variant	Exon 36 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4373C>T	p.Thr1458Met	missense_variant	Exon 35 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4364C>T	p.Thr1455Met	missense_variant	Exon 35 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4289C>T	p.Thr1430Met	missense_variant	Exon 34 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4289C>T	p.Thr1430Met	missense_variant	Exon 34 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4283C>T	p.Thr1428Met	missense_variant	Exon 34 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4322C>T	p.Thr1441Met	missense_variant	Exon 35 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4313C>T	p.Thr1438Met	missense_variant	Exon 35 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4289C>T	p.Thr1430Met	missense_variant	Exon 34 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0175

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249582 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135294

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461632 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727076

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: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74364

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.000174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Apr 20, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with suspected Brugada syndrome in published literature; however, detailed clinical information was not provided (Marschall et al., 2019); This variant is associated with the following publications: (PMID: 31737537) -

Long QT syndrome Uncertain:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1441 of the CACNA1C protein (p.Thr1441Met). This variant is present in population databases (rs727503835, gnomAD 0.004%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 166773). Invitae Evidence 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 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. 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 Benign:1

May 05, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.022	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	0.92	D
MutationAssessor	Benign	1.7	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.46
Sift	Benign	0.099	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.098	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.96, 0.91, 0.89, 0.96, 0.95, 0.98, 0.88, 0.98, 1.0, 0.97	.;D;P;P;P;P;D;D;P;P;D;D;D;D;D;.;D;D;.;.;.;P;.
Vest4		0.30
MVP		0.75
MPC		1.2
ClinPred		0.64	D
GERP RS		4.1
gMVP		0.63

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: rs727503835; hg19: chr12-2774080; COSMIC: COSV104404970; COSMIC: COSV104404970;