rs56270948

Positions:

• chr12-2685811-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5649G>A​(p.Pro1883Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,556,064 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (34 hom., cov: 32)
  • Exomes 𝑓: 0.020 (311 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.308

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-2685811-G-A is Benign according to our data. Variant chr12-2685811-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2685811-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0167 (2485/148444) while in subpopulation EAS AF= 0.0384 (198/5154). AF 95% confidence interval is 0.034. There are 34 homozygotes in gnomad4. There are 1210 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2485 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5988G>A	p.Pro1996Pro	synonymous_variant	47/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5862G>A	p.Pro1954Pro	synonymous_variant	45/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5829G>A	p.Pro1943Pro	synonymous_variant	44/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5814G>A	p.Pro1938Pro	synonymous_variant	45/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5793G>A	p.Pro1931Pro	synonymous_variant	46/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5772G>A	p.Pro1924Pro	synonymous_variant	44/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5754G>A	p.Pro1918Pro	synonymous_variant	45/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5754G>A	p.Pro1918Pro	synonymous_variant	45/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5739G>A	p.Pro1913Pro	synonymous_variant	44/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5739G>A	p.Pro1913Pro	synonymous_variant	44/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5739G>A	p.Pro1913Pro	synonymous_variant	44/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5739G>A	p.Pro1913Pro	synonymous_variant	44/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5733G>A	p.Pro1911Pro	synonymous_variant	45/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5724G>A	p.Pro1908Pro	synonymous_variant	45/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5709G>A	p.Pro1903Pro	synonymous_variant	45/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5706G>A	p.Pro1902Pro	synonymous_variant	44/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5706G>A	p.Pro1902Pro	synonymous_variant	44/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5706G>A	p.Pro1902Pro	synonymous_variant	44/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5700G>A	p.Pro1900Pro	synonymous_variant	44/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5691G>A	p.Pro1897Pro	synonymous_variant	44/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5673G>A	p.Pro1891Pro	synonymous_variant	43/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5673G>A	p.Pro1891Pro	synonymous_variant	43/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5667G>A	p.Pro1889Pro	synonymous_variant	43/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5649G>A	p.Pro1883Pro	synonymous_variant	44/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5640G>A	p.Pro1880Pro	synonymous_variant	44/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5616G>A	p.Pro1872Pro	synonymous_variant	43/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2488 AN: 148338 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00935

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.00610

Gnomad FIN AF: 0.0268

Gnomad MID AF: 0.0129

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0147

GnomAD3 exomes AF: 0.0207 AC: 4973 AN: 239870 Hom.: 63 AF XY: 0.0197 AC XY: 2573 AN XY: 130394

Gnomad AFR exome AF: 0.0226

Gnomad AMR exome AF: 0.00914

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.0410

Gnomad SAS exome AF: 0.00484

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0236

Gnomad OTH exome AF: 0.0216

GnomAD4 exome AF: 0.0203 AC: 28550 AN: 1407620 Hom.: 311 Cov.: 31 AF XY: 0.0196 AC XY: 13755 AN XY: 701650

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00894

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.0278

Gnomad4 SAS exome AF: 0.00479

Gnomad4 FIN exome AF: 0.0262

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0202

GnomAD4 genome AF: 0.0167 AC: 2485 AN: 148444 Hom.: 34 Cov.: 32 AF XY: 0.0167 AC XY: 1210 AN XY: 72510

Gnomad4 AFR AF: 0.00932

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.0384

Gnomad4 SAS AF: 0.00589

Gnomad4 FIN AF: 0.0268

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0146

Alfa AF: 0.0218 Hom.: 12

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2015

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_noAF	Benign	-0.63
CADD	Benign	3.8
DANN	Benign	0.87

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: rs56270948; hg19: chr12-2794977; COSMIC: COSV59745588; COSMIC: COSV59745588;