rs1453566638

Positions:

• chr12-2581683-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000719.7(CACNA1C):​c.1989C>T​(p.Ile663Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000124 in 1,611,924 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: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.11

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 12-2581683-C-T is Benign according to our data. Variant chr12-2581683-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456950.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2079C>T	p.Ile693Ile	synonymous_variant	14/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1989C>T	p.Ile663Ile	synonymous_variant	14/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2154C>T	p.Ile718Ile	synonymous_variant	15/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1989C>T	p.Ile663Ile	synonymous_variant	14/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1989C>T	p.Ile663Ile	synonymous_variant	14/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1989C>T	p.Ile663Ile	synonymous_variant	14/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2079C>T	p.Ile693Ile	synonymous_variant	14/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2079C>T	p.Ile693Ile	synonymous_variant	14/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2079C>T	p.Ile693Ile	synonymous_variant	14/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2079C>T	p.Ile693Ile	synonymous_variant	14/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2064C>T	p.Ile688Ile	synonymous_variant	15/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2064C>T	p.Ile688Ile	synonymous_variant	15/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1989C>T	p.Ile663Ile	synonymous_variant	14/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1980C>T	p.Ile660Ile	synonymous_variant	14/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1989C>T	p.Ile663Ile	synonymous_variant	14/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*596C>T		non_coding_transcript_exon_variant	12/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*596C>T		3_prime_UTR_variant	12/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 29

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459816 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726044

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 AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1453566638; hg19: chr12-2690849; COSMIC: COSV105227241; COSMIC: COSV105227241;