rs1417477759

Positions:

• chr12-2449107-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6 BP7 BS2

The NM_000719.7(CACNA1C):​c.609G>A​(p.Val203Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,393,194 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.92

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]

ENSG00000285734 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-2449107-G-A is Benign according to our data. Variant chr12-2449107-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=2.92 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.609G>A	p.Val203Val	synonymous_variant	4/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.609G>A	p.Val203Val	synonymous_variant	4/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.609G>A	p.Val203Val	synonymous_variant	4/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.609G>A	p.Val203Val	synonymous_variant	4/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.699G>A	p.Val233Val	synonymous_variant	4/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.609G>A	p.Val203Val	synonymous_variant	4/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.609G>A	p.Val203Val	synonymous_variant	4/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.699G>A	p.Val233Val	synonymous_variant	4/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.609G>A	p.Val203Val	synonymous_variant	4/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.609G>A	p.Val203Val	synonymous_variant	4/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.609G>A	p.Val203Val	synonymous_variant	4/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.699G>A	p.Val233Val	synonymous_variant	4/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.699G>A	p.Val233Val	synonymous_variant	4/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.699G>A	p.Val233Val	synonymous_variant	4/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.699G>A	p.Val233Val	synonymous_variant	4/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.609G>A	p.Val203Val	synonymous_variant	4/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.609G>A	p.Val203Val	synonymous_variant	4/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.609G>A	p.Val203Val	synonymous_variant	4/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.609G>A	p.Val203Val	synonymous_variant	4/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.609G>A	p.Val203Val	synonymous_variant	4/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.609G>A	p.Val203Val	synonymous_variant	4/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.609G>A	p.Val203Val	synonymous_variant	4/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.609G>A	p.Val203Val	synonymous_variant	4/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.609G>A	p.Val203Val	synonymous_variant	4/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.609G>A	p.Val203Val	synonymous_variant	4/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.609G>A	p.Val203Val	synonymous_variant	4/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.558G>A	p.Val186Val	synonymous_variant	3/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.609G>A		non_coding_transcript_exon_variant	4/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000641 AC: 1 AN: 155966 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81512

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000885

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1393194 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 686904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.0000131

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 09, 2020

The CACNA1C c.609G>A; p.Val203= variant (rs1417477759), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 526913). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site/weakening the nearby canonical site. However, given the lack of clinical and functional data, the significance of the p.Val203= variant is uncertain at this time. Gene statement: Pathogenic variants in CACNA1C are associated with autosomal dominant Timothy syndrome (MIM: 601005) and Brugada syndrome 3 (MIM: 611875). -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 29, 2022

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	-0.46
CADD	Benign	12
DANN	Benign	0.80

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: rs1417477759; hg19: chr12-2558273;