12-2668938-G-A

Variant names:

• chr12-2668938-G-A
• rs2096394166
• NM_000719.7:c.4629G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000719.7(CACNA1C):​c.4629G>A​(p.Leu1543Leu) 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 1,461,038 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.372

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-AS2 (HGNC:):

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

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=-0.3).
• BP6: Variant 12-2668938-G-A is Benign according to our data. Variant chr12-2668938-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1741995.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.372 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4863G>A	p.Leu1621Leu	synonymous_variant	Exon 40 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4596G>A	p.Leu1532Leu	synonymous_variant	Exon 37 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4794G>A	p.Leu1598Leu	synonymous_variant	Exon 39 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4773G>A	p.Leu1591Leu	synonymous_variant	Exon 40 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4695G>A	p.Leu1565Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4719G>A	p.Leu1573Leu	synonymous_variant	Exon 38 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4719G>A	p.Leu1573Leu	synonymous_variant	Exon 38 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4719G>A	p.Leu1573Leu	synonymous_variant	Exon 38 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4719G>A	p.Leu1573Leu	synonymous_variant	Exon 38 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4713G>A	p.Leu1571Leu	synonymous_variant	Exon 39 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4704G>A	p.Leu1568Leu	synonymous_variant	Exon 39 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4689G>A	p.Leu1563Leu	synonymous_variant	Exon 39 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4680G>A	p.Leu1560Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4671G>A	p.Leu1557Leu	synonymous_variant	Exon 38 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4596G>A	p.Leu1532Leu	synonymous_variant	Exon 37 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4596G>A	p.Leu1532Leu	synonymous_variant	Exon 37 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4590G>A	p.Leu1530Leu	synonymous_variant	Exon 37 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4629G>A	p.Leu1543Leu	synonymous_variant	Exon 38 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4620G>A	p.Leu1540Leu	synonymous_variant	Exon 38 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4596G>A	p.Leu1532Leu	synonymous_variant	Exon 37 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461038 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726854

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Benign:1

Jun 12, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.30
CADD	Benign	15
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2096394166; hg19: chr12-2778104;