12-2585466-G-T

Position:

• chr12-2585466-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000719.7(CACNA1C):​c.2430G>T​(p.Thr810Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,425,118 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 (★). Synonymous variant affecting the same amino acid position (i.e. T810T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.87

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-2585466-G-T is Benign according to our data. Variant chr12-2585466-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2731169.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-2585466-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.87 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2520G>T	p.Thr840Thr	synonymous_variant	17/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2430G>T	p.Thr810Thr	synonymous_variant	17/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2595G>T	p.Thr865Thr	synonymous_variant	18/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2430G>T	p.Thr810Thr	synonymous_variant	17/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2430G>T	p.Thr810Thr	synonymous_variant	17/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2430G>T	p.Thr810Thr	synonymous_variant	17/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2520G>T	p.Thr840Thr	synonymous_variant	17/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2520G>T	p.Thr840Thr	synonymous_variant	17/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2520G>T	p.Thr840Thr	synonymous_variant	17/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2520G>T	p.Thr840Thr	synonymous_variant	17/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2505G>T	p.Thr835Thr	synonymous_variant	18/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2505G>T	p.Thr835Thr	synonymous_variant	18/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2430G>T	p.Thr810Thr	synonymous_variant	17/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2421G>T	p.Thr807Thr	synonymous_variant	17/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2430G>T	p.Thr810Thr	synonymous_variant	17/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1037G>T		non_coding_transcript_exon_variant	15/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1037G>T		3_prime_UTR_variant	15/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000107 AC: 2 AN: 186368 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 100108

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: 0.0000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1425118 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705758

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: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000283 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

Nov 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.016
DANN	Benign	0.47

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: rs775571017; hg19: chr12-2694632;