12-2691052-C-T

Variant names:

• chr12-2691052-C-T
• rs1060504921
• NM_000719.7:c.6270C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000719.7(CACNA1C):​c.6270C>T​(p.Pro2090Pro) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000657 in 152,148 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.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6609C>T	p.Pro2203Pro	synonymous_variant	Exon 50 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6483C>T	p.Pro2161Pro	synonymous_variant	Exon 48 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6450C>T	p.Pro2150Pro	synonymous_variant	Exon 47 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6435C>T	p.Pro2145Pro	synonymous_variant	Exon 48 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6414C>T	p.Pro2138Pro	synonymous_variant	Exon 49 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6393C>T	p.Pro2131Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6375C>T	p.Pro2125Pro	synonymous_variant	Exon 48 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6375C>T	p.Pro2125Pro	synonymous_variant	Exon 48 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6360C>T	p.Pro2120Pro	synonymous_variant	Exon 47 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6360C>T	p.Pro2120Pro	synonymous_variant	Exon 47 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6360C>T	p.Pro2120Pro	synonymous_variant	Exon 47 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6360C>T	p.Pro2120Pro	synonymous_variant	Exon 47 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6354C>T	p.Pro2118Pro	synonymous_variant	Exon 48 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6345C>T	p.Pro2115Pro	synonymous_variant	Exon 48 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6330C>T	p.Pro2110Pro	synonymous_variant	Exon 48 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6327C>T	p.Pro2109Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6327C>T	p.Pro2109Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6327C>T	p.Pro2109Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6321C>T	p.Pro2107Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6312C>T	p.Pro2104Pro	synonymous_variant	Exon 47 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6294C>T	p.Pro2098Pro	synonymous_variant	Exon 46 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6294C>T	p.Pro2098Pro	synonymous_variant	Exon 46 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6288C>T	p.Pro2096Pro	synonymous_variant	Exon 46 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6270C>T	p.Pro2090Pro	synonymous_variant	Exon 47 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6261C>T	p.Pro2087Pro	synonymous_variant	Exon 47 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6237C>T	p.Pro2079Pro	synonymous_variant	Exon 46 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000432 AC: 1 AN: 231296 Hom.: 0 AF XY: 0.00000791 AC XY: 1 AN XY: 126350

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: 0.00

Gnomad OTH exome AF: 0.000176

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454398 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 722882

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

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

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060504921; hg19: chr12-2800218; COSMIC: COSV59697018; COSMIC: COSV59697018;