rs370145265

Variant names:

• chr12-2584510-A-C
• rs370145265
• NM_000719.7:c.2232A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.2232A>C​(p.Leu744Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,609,672 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.122
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 12-2584510-A-C is Benign according to our data. Variant chr12-2584510-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 308137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.122 with no splicing effect.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2232A>C	p.Leu744Leu	synonymous_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.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2322A>C	p.Leu774Leu	synonymous_variant	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2397A>C	p.Leu799Leu	synonymous_variant	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2322A>C	p.Leu774Leu	synonymous_variant	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2322A>C	p.Leu774Leu	synonymous_variant	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2322A>C	p.Leu774Leu	synonymous_variant	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2322A>C	p.Leu774Leu	synonymous_variant	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2307A>C	p.Leu769Leu	synonymous_variant	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2307A>C	p.Leu769Leu	synonymous_variant	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2223A>C	p.Leu741Leu	synonymous_variant	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2232A>C	p.Leu744Leu	synonymous_variant	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*839A>C		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*839A>C		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249168 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000494 AC: 72 AN: 1457498 Hom.: 0 Cov.: 29 AF XY: 0.0000386 AC XY: 28 AN XY: 725372

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000623 AC: 69 AN: 1108140

Other (OTH) AF: 0.0000332 AC: 2 AN: 60228

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74344

African (AFR) AF: 0.0000966 AC: 4 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 09, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Long QT syndrome Benign:1

Dec 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Sep 11, 2019

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_noAF	Benign	-0.52
CADD	Benign	9.7
DANN	Benign	0.80
PhyloP100		-0.12
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs370145265; hg19: chr12-2693676;