rs141633456

Variant names:

• chr12-2584558-G-A
• rs141633456
• NM_000719.7:c.2280G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.2280G>A​(p.Glu760Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00034 in 1,613,820 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 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.35
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-2584558-G-A is Benign according to our data. Variant chr12-2584558-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93396.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000237 (36/152206) while in subpopulation NFE AF = 0.00047 (32/68042). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2280G>A	p.Glu760Glu	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.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2370G>A	p.Glu790Glu	synonymous_variant	Exon 16 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2445G>A	p.Glu815Glu	synonymous_variant	Exon 17 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2370G>A	p.Glu790Glu	synonymous_variant	Exon 16 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2370G>A	p.Glu790Glu	synonymous_variant	Exon 16 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2370G>A	p.Glu790Glu	synonymous_variant	Exon 16 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2370G>A	p.Glu790Glu	synonymous_variant	Exon 16 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2355G>A	p.Glu785Glu	synonymous_variant	Exon 17 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2355G>A	p.Glu785Glu	synonymous_variant	Exon 17 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2271G>A	p.Glu757Glu	synonymous_variant	Exon 16 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2280G>A	p.Glu760Glu	synonymous_variant	Exon 16 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*887G>A		non_coding_transcript_exon_variant	Exon 14 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*887G>A		3_prime_UTR_variant	Exon 14 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

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: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000181 AC: 45 AN: 249160 AF XY: 0.000207

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000363

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000350 AC: 512 AN: 1461614 Hom.: 0 Cov.: 30 AF XY: 0.000366 AC XY: 266 AN XY: 727082

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000443 AC: 493 AN: 1111838

Other (OTH) AF: 0.000298 AC: 18 AN: 60370

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74364

African (AFR) AF: 0.0000965 AC: 4 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68042

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

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000223

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4, BS2 -

Sep 26, 2012

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Nov 22, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 26, 2016

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	-0.31
CADD	Benign	11
DANN	Benign	0.65
PhyloP100		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs141633456; hg19: chr12-2693724;