rs373253192

Positions:

• chr12-2688668-C-G
• chr12-2688668-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000719.7(CACNA1C):​c.6006C>G​(p.Gly2002Gly) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 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=-0.8).
• BP7: Synonymous conserved (PhyloP=-0.897 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6006C>G	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>G	p.Gly2002Gly	synonymous_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6345C>G	p.Gly2115Gly	synonymous_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6219C>G	p.Gly2073Gly	synonymous_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6186C>G	p.Gly2062Gly	synonymous_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6171C>G	p.Gly2057Gly	synonymous_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6150C>G	p.Gly2050Gly	synonymous_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6129C>G	p.Gly2043Gly	synonymous_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6111C>G	p.Gly2037Gly	synonymous_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6111C>G	p.Gly2037Gly	synonymous_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6096C>G	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6096C>G	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6096C>G	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6096C>G	p.Gly2032Gly	synonymous_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6090C>G	p.Gly2030Gly	synonymous_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6081C>G	p.Gly2027Gly	synonymous_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6066C>G	p.Gly2022Gly	synonymous_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6063C>G	p.Gly2021Gly	synonymous_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6063C>G	p.Gly2021Gly	synonymous_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6063C>G	p.Gly2021Gly	synonymous_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6057C>G	p.Gly2019Gly	synonymous_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6048C>G	p.Gly2016Gly	synonymous_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6030C>G	p.Gly2010Gly	synonymous_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6030C>G	p.Gly2010Gly	synonymous_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6024C>G	p.Gly2008Gly	synonymous_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6006C>G	p.Gly2002Gly	synonymous_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5997C>G	p.Gly1999Gly	synonymous_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5973C>G	p.Gly1991Gly	synonymous_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246770 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134296

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: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.23
DANN	Benign	0.50

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;