12-2688668-C-T

Position:

• chr12-2688668-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.6006C>T​(p.Gly2002Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,342 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: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.897

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=-0.74).
• BP6: Variant 12-2688668-C-T is Benign according to our data. Variant chr12-2688668-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.897 with no splicing effect.
• BS2: High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6345C>T	p.Gly2115Gly	synonymous_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6219C>T	p.Gly2073Gly	synonymous_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6186C>T	p.Gly2062Gly	synonymous_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6171C>T	p.Gly2057Gly	synonymous_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6150C>T	p.Gly2050Gly	synonymous_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6129C>T	p.Gly2043Gly	synonymous_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6111C>T	p.Gly2037Gly	synonymous_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6111C>T	p.Gly2037Gly	synonymous_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6096C>T	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6096C>T	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6096C>T	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6096C>T	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6090C>T	p.Gly2030Gly	synonymous_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6081C>T	p.Gly2027Gly	synonymous_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6066C>T	p.Gly2022Gly	synonymous_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6063C>T	p.Gly2021Gly	synonymous_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6063C>T	p.Gly2021Gly	synonymous_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6063C>T	p.Gly2021Gly	synonymous_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6057C>T	p.Gly2019Gly	synonymous_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6048C>T	p.Gly2016Gly	synonymous_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6030C>T	p.Gly2010Gly	synonymous_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6030C>T	p.Gly2010Gly	synonymous_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6024C>T	p.Gly2008Gly	synonymous_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6006C>T	p.Gly2002Gly	synonymous_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5997C>T	p.Gly1999Gly	synonymous_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5973C>T	p.Gly1991Gly	synonymous_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000608 AC: 15 AN: 246770 Hom.: 0 AF XY: 0.0000670 AC XY: 9 AN XY: 134296

Gnomad AFR exome AF: 0.000659

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461162 Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17 AN XY: 726926

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000134

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: 0.00000899

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74340

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000204

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Jan 28, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2017

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	-0.74
CADD	Benign	1.0
DANN	Benign	0.67

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: rs373253192; hg19: chr12-2797834;