rs863224373

Positions:

• chr12-2677810-G-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.5034G>A​(p.Glu1678Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,678 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: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.39

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:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

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=-0.46).
• BP6: Variant 12-2677810-G-A is Benign according to our data. Variant chr12-2677810-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 215770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.39 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5268G>A	p.Glu1756Glu	synonymous_variant	43/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5001G>A	p.Glu1667Glu	synonymous_variant	40/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5199G>A	p.Glu1733Glu	synonymous_variant	42/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5178G>A	p.Glu1726Glu	synonymous_variant	43/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5157G>A	p.Glu1719Glu	synonymous_variant	41/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5124G>A	p.Glu1708Glu	synonymous_variant	41/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5124G>A	p.Glu1708Glu	synonymous_variant	41/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5124G>A	p.Glu1708Glu	synonymous_variant	41/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5124G>A	p.Glu1708Glu	synonymous_variant	41/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5118G>A	p.Glu1706Glu	synonymous_variant	42/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5109G>A	p.Glu1703Glu	synonymous_variant	42/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5094G>A	p.Glu1698Glu	synonymous_variant	42/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5091G>A	p.Glu1697Glu	synonymous_variant	41/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5091G>A	p.Glu1697Glu	synonymous_variant	41/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5091G>A	p.Glu1697Glu	synonymous_variant	41/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5085G>A	p.Glu1695Glu	synonymous_variant	41/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5076G>A	p.Glu1692Glu	synonymous_variant	41/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5058G>A	p.Glu1686Glu	synonymous_variant	40/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5058G>A	p.Glu1686Glu	synonymous_variant	40/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5052G>A	p.Glu1684Glu	synonymous_variant	40/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5034G>A	p.Glu1678Glu	synonymous_variant	41/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5025G>A	p.Glu1675Glu	synonymous_variant	41/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5001G>A	p.Glu1667Glu	synonymous_variant	40/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727126

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000611 Hom.: 0

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

Apr 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.59

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: rs863224373; hg19: chr12-2786976;