rs1231791018

Positions:

• chr12-2679602-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.5250C>T​(p.Asp1750Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000151 in 1,461,486 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: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.751

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-2679602-C-T is Benign according to our data. Variant chr12-2679602-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.751 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5484C>T	p.Asp1828Asp	synonymous_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5217C>T	p.Asp1739Asp	synonymous_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5415C>T	p.Asp1805Asp	synonymous_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5394C>T	p.Asp1798Asp	synonymous_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5373C>T	p.Asp1791Asp	synonymous_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5340C>T	p.Asp1780Asp	synonymous_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5340C>T	p.Asp1780Asp	synonymous_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5340C>T	p.Asp1780Asp	synonymous_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5340C>T	p.Asp1780Asp	synonymous_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5334C>T	p.Asp1778Asp	synonymous_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5325C>T	p.Asp1775Asp	synonymous_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5310C>T	p.Asp1770Asp	synonymous_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5307C>T	p.Asp1769Asp	synonymous_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5307C>T	p.Asp1769Asp	synonymous_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5307C>T	p.Asp1769Asp	synonymous_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5301C>T	p.Asp1767Asp	synonymous_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5292C>T	p.Asp1764Asp	synonymous_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5274C>T	p.Asp1758Asp	synonymous_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5274C>T	p.Asp1758Asp	synonymous_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5268C>T	p.Asp1756Asp	synonymous_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5250C>T	p.Asp1750Asp	synonymous_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5241C>T	p.Asp1747Asp	synonymous_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5217C>T	p.Asp1739Asp	synonymous_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247606 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134510

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: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461486 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

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: 0.0000198

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 02, 2017

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2019

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	-0.50
CADD	Benign	8.4
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: rs1231791018; hg19: chr12-2788768;