rs776532518

Variant names:

• chr12-2120409-C-T
• rs776532518
• NM_000719.7:c.456C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000719.7(CACNA1C):​c.456C>T​(p.Ser152Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,646 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: 33)
  • 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: 2.89

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-2120409-C-T is Benign according to our data. Variant chr12-2120409-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 456971.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.546C>T	p.Ser182Ser	synonymous_variant	Exon 3 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.546C>T	p.Ser182Ser	synonymous_variant	Exon 3 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.546C>T	p.Ser182Ser	synonymous_variant	Exon 3 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.546C>T	p.Ser182Ser	synonymous_variant	Exon 3 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.546C>T	p.Ser182Ser	synonymous_variant	Exon 3 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.546C>T	p.Ser182Ser	synonymous_variant	Exon 3 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.456C>T	p.Ser152Ser	synonymous_variant	Exon 3 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.405C>T	p.Ser135Ser	synonymous_variant	Exon 2 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.456C>T		non_coding_transcript_exon_variant	Exon 3 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249316 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000555

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: 6.88e-7 AC: 1 AN: 1453646 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723706

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: 0.0000166

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Feb 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	12
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: 21

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

Publications

LitVar

Other links and lift over

dbSNP: rs776532518; hg19: chr12-2229575;