12-2679698-C-T

Position:

• chr12-2679698-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.5346C>T​(p.Ala1782Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,611,710 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A1782A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.173

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 12-2679698-C-T is Benign according to our data. Variant chr12-2679698-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 527056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.173 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000105 (16/152228) while in subpopulation AMR AF= 0.00085 (13/15292). AF 95% confidence interval is 0.000502. There are 1 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5346C>T	p.Ala1782Ala	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.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5580C>T	p.Ala1860Ala	synonymous_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5313C>T	p.Ala1771Ala	synonymous_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5511C>T	p.Ala1837Ala	synonymous_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5490C>T	p.Ala1830Ala	synonymous_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5469C>T	p.Ala1823Ala	synonymous_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5436C>T	p.Ala1812Ala	synonymous_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5436C>T	p.Ala1812Ala	synonymous_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5436C>T	p.Ala1812Ala	synonymous_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5436C>T	p.Ala1812Ala	synonymous_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5430C>T	p.Ala1810Ala	synonymous_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5421C>T	p.Ala1807Ala	synonymous_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5406C>T	p.Ala1802Ala	synonymous_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5403C>T	p.Ala1801Ala	synonymous_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5403C>T	p.Ala1801Ala	synonymous_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5403C>T	p.Ala1801Ala	synonymous_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5397C>T	p.Ala1799Ala	synonymous_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5388C>T	p.Ala1796Ala	synonymous_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5370C>T	p.Ala1790Ala	synonymous_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5370C>T	p.Ala1790Ala	synonymous_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5364C>T	p.Ala1788Ala	synonymous_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5346C>T	p.Ala1782Ala	synonymous_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5337C>T	p.Ala1779Ala	synonymous_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5313C>T	p.Ala1771Ala	synonymous_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000248 AC: 6 AN: 241626 Hom.: 0 AF XY: 0.0000304 AC XY: 4 AN XY: 131420

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000564

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1459482 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 725822

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152228 Hom.: 1 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74366

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000956

Bravo AF: 0.000196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 23, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 05, 2020

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	-0.75
CADD	Benign	1.7
DANN	Benign	0.83

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: rs369254461; hg19: chr12-2788864; COSMIC: COSV100215419; COSMIC: COSV100215419;