rs776884902

Positions:

• chr12-2610636-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_000719.7(CACNA1C):​c.3654C>T​(p.Ser1218Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,461,872 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: 0.000047 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.57

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 Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-2610636-C-T is Benign according to our data. Variant chr12-2610636-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 416850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2610636-C-T is described in Lovd as [Benign]. Variant chr12-2610636-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.57 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3804C>T	p.Ser1268Ser	synonymous_variant	29/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3819C>T	p.Ser1273Ser	synonymous_variant	29/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3714C>T	p.Ser1238Ser	synonymous_variant	29/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3744C>T	p.Ser1248Ser	synonymous_variant	28/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3744C>T	p.Ser1248Ser	synonymous_variant	28/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3744C>T	p.Ser1248Ser	synonymous_variant	28/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3744C>T	p.Ser1248Ser	synonymous_variant	28/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3729C>T	p.Ser1243Ser	synonymous_variant	29/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3714C>T	p.Ser1238Ser	synonymous_variant	29/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3729C>T	p.Ser1243Ser	synonymous_variant	29/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3645C>T	p.Ser1215Ser	synonymous_variant	28/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3654C>T	p.Ser1218Ser	synonymous_variant	28/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2261C>T		non_coding_transcript_exon_variant	26/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2261C>T		3_prime_UTR_variant	26/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 250614 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135704

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 68 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2015	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2017

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	-0.31
CADD	Benign	11
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs776884902; hg19: chr12-2719802; COSMIC: COSV59701494; COSMIC: COSV59701494;