12-2611965-C-T

Position:

• chr12-2611965-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000719.7(CACNA1C):​c.3780C>T​(p.Gly1260Gly) 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 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1260G) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP7: Synonymous conserved (PhyloP=0.13 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3930C>T	p.Gly1310Gly	synonymous_variant	30/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3945C>T	p.Gly1315Gly	synonymous_variant	30/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3840C>T	p.Gly1280Gly	synonymous_variant	30/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3870C>T	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3870C>T	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3870C>T	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3870C>T	p.Gly1290Gly	synonymous_variant	29/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3855C>T	p.Gly1285Gly	synonymous_variant	30/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3840C>T	p.Gly1280Gly	synonymous_variant	30/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3855C>T	p.Gly1285Gly	synonymous_variant	30/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3771C>T	p.Gly1257Gly	synonymous_variant	29/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3780C>T	p.Gly1260Gly	synonymous_variant	29/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2387C>T		non_coding_transcript_exon_variant	27/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2387C>T		3_prime_UTR_variant	27/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250230 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461278 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.6
DANN	Benign	0.76

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: rs201258230; hg19: chr12-2721131;