12-2666692-T-G

Position:

• chr12-2666692-T-G

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.4533T>G​(p.Arg1511Arg) 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: 32)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92

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=-0.7).
• BP7: Synonymous conserved (PhyloP=-1.92 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4767T>G	p.Arg1589Arg	synonymous_variant	39/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4500T>G	p.Arg1500Arg	synonymous_variant	36/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4698T>G	p.Arg1566Arg	synonymous_variant	38/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4677T>G	p.Arg1559Arg	synonymous_variant	39/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4599T>G	p.Arg1533Arg	synonymous_variant	37/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4623T>G	p.Arg1541Arg	synonymous_variant	37/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4623T>G	p.Arg1541Arg	synonymous_variant	37/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4623T>G	p.Arg1541Arg	synonymous_variant	37/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4623T>G	p.Arg1541Arg	synonymous_variant	37/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4617T>G	p.Arg1539Arg	synonymous_variant	38/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4608T>G	p.Arg1536Arg	synonymous_variant	38/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4593T>G	p.Arg1531Arg	synonymous_variant	38/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4584T>G	p.Arg1528Arg	synonymous_variant	37/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4575T>G	p.Arg1525Arg	synonymous_variant	37/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4500T>G	p.Arg1500Arg	synonymous_variant	36/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4500T>G	p.Arg1500Arg	synonymous_variant	36/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4494T>G	p.Arg1498Arg	synonymous_variant	36/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4533T>G	p.Arg1511Arg	synonymous_variant	37/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4524T>G	p.Arg1508Arg	synonymous_variant	37/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4500T>G	p.Arg1500Arg	synonymous_variant	36/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.0
DANN	Benign	0.74

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: rs1060504920; hg19: chr12-2775858;