chr12-2691058-C-A

Position:

• chr12-2691058-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000719.7(CACNA1C):​c.6276C>A​(p.Gly2092Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.08

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-AS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 12-2691058-C-A is Benign according to our data. Variant chr12-2691058-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 527072.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6615C>A	p.Gly2205Gly	synonymous_variant	50/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6489C>A	p.Gly2163Gly	synonymous_variant	48/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6456C>A	p.Gly2152Gly	synonymous_variant	47/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6441C>A	p.Gly2147Gly	synonymous_variant	48/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6420C>A	p.Gly2140Gly	synonymous_variant	49/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6399C>A	p.Gly2133Gly	synonymous_variant	47/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6381C>A	p.Gly2127Gly	synonymous_variant	48/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6381C>A	p.Gly2127Gly	synonymous_variant	48/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6366C>A	p.Gly2122Gly	synonymous_variant	47/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6366C>A	p.Gly2122Gly	synonymous_variant	47/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6366C>A	p.Gly2122Gly	synonymous_variant	47/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6366C>A	p.Gly2122Gly	synonymous_variant	47/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6360C>A	p.Gly2120Gly	synonymous_variant	48/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6351C>A	p.Gly2117Gly	synonymous_variant	48/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6336C>A	p.Gly2112Gly	synonymous_variant	48/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6333C>A	p.Gly2111Gly	synonymous_variant	47/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6333C>A	p.Gly2111Gly	synonymous_variant	47/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6333C>A	p.Gly2111Gly	synonymous_variant	47/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6327C>A	p.Gly2109Gly	synonymous_variant	47/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6318C>A	p.Gly2106Gly	synonymous_variant	47/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6300C>A	p.Gly2100Gly	synonymous_variant	46/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6300C>A	p.Gly2100Gly	synonymous_variant	46/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6294C>A	p.Gly2098Gly	synonymous_variant	46/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6276C>A	p.Gly2092Gly	synonymous_variant	47/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6267C>A	p.Gly2089Gly	synonymous_variant	47/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6243C>A	p.Gly2081Gly	synonymous_variant	46/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455208 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723376

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	13
DANN	Benign	0.94

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: rs1556333950; hg19: chr12-2800224;