rs758229132

Positions:

• chr12-2115514-C-A
• chr12-2115514-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.340C>A​(p.Arg114Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.37

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 12-2115514-C-A is Benign according to our data. Variant chr12-2115514-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 527091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000267 (39/1461100) while in subpopulation AMR AF= 0.000693 (31/44724). AF 95% confidence interval is 0.000502. There are 1 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.430C>A	p.Arg144Arg	synonymous_variant	2/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.340C>A	p.Arg114Arg	synonymous_variant	2/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.430C>A	p.Arg144Arg	synonymous_variant	2/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.340C>A	p.Arg114Arg	synonymous_variant	2/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.340C>A	p.Arg114Arg	synonymous_variant	2/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.340C>A	p.Arg114Arg	synonymous_variant	2/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.430C>A	p.Arg144Arg	synonymous_variant	2/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.430C>A	p.Arg144Arg	synonymous_variant	2/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.430C>A	p.Arg144Arg	synonymous_variant	2/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.430C>A	p.Arg144Arg	synonymous_variant	2/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.340C>A	p.Arg114Arg	synonymous_variant	2/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.340C>A	p.Arg114Arg	synonymous_variant	2/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.340C>A	p.Arg114Arg	synonymous_variant	2/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.340C>A	p.Arg114Arg	synonymous_variant	2/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.340C>A	p.Arg114Arg	synonymous_variant	2/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.340C>A	p.Arg114Arg	synonymous_variant	2/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.289C>A	p.Arg97Arg	synonymous_variant	1/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.340C>A		non_coding_transcript_exon_variant	2/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.000122 AC: 30 AN: 246874 Hom.: 1 AF XY: 0.0000521 AC XY: 7 AN XY: 134430

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000811

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: 0.00

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461100 Hom.: 1 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 726872

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000693

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 34

Bravo AF: 0.0000151

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2023

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	-0.19
CADD	Benign	9.9
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758229132; hg19: chr12-2224680;