rs369673473

Positions:

• chr12-2449035-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.537C>T​(p.Ile179Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000837 in 1,601,044 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 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0690

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]

ENSG00000285734 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 12-2449035-C-T is Benign according to our data. Variant chr12-2449035-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 308128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.069 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000434 (66/152152) while in subpopulation AFR AF= 0.00133 (55/41422). AF 95% confidence interval is 0.00105. There are 0 homozygotes in gnomad4. There are 31 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 66 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.627C>T	p.Ile209Ile	synonymous_variant	4/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.537C>T	p.Ile179Ile	synonymous_variant	4/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.627C>T	p.Ile209Ile	synonymous_variant	4/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.537C>T	p.Ile179Ile	synonymous_variant	4/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.537C>T	p.Ile179Ile	synonymous_variant	4/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.537C>T	p.Ile179Ile	synonymous_variant	4/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.627C>T	p.Ile209Ile	synonymous_variant	4/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.627C>T	p.Ile209Ile	synonymous_variant	4/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.627C>T	p.Ile209Ile	synonymous_variant	4/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.627C>T	p.Ile209Ile	synonymous_variant	4/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.537C>T	p.Ile179Ile	synonymous_variant	4/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.537C>T	p.Ile179Ile	synonymous_variant	4/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.537C>T	p.Ile179Ile	synonymous_variant	4/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.537C>T	p.Ile179Ile	synonymous_variant	4/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.537C>T	p.Ile179Ile	synonymous_variant	4/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.537C>T	p.Ile179Ile	synonymous_variant	4/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.486C>T	p.Ile162Ile	synonymous_variant	3/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.537C>T		non_coding_transcript_exon_variant	4/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152152 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000115 AC: 27 AN: 235418 Hom.: 0 AF XY: 0.000102 AC XY: 13 AN XY: 127240

Gnomad AFR exome AF: 0.000881

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000353

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 68 AN: 1448892 Hom.: 0 Cov.: 28 AF XY: 0.0000389 AC XY: 28 AN XY: 720222

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.000161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000997

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000434 AC: 66 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74316

Gnomad4 AFR AF: 0.00133

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2016

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	-0.32
CADD	Benign	12
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs369673473; hg19: chr12-2558201; COSMIC: COSV59717579;