rs370576211

Positions:

• chr12-2611932-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.3747C>T​(p.Ile1249Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,613,346 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0430

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 12-2611932-C-T is Benign according to our data. Variant chr12-2611932-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256766.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-0.043 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000256 (39/152262) while in subpopulation AFR AF= 0.000818 (34/41556). AF 95% confidence interval is 0.000601. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3897C>T	p.Ile1299Ile	synonymous_variant	30/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3912C>T	p.Ile1304Ile	synonymous_variant	30/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3807C>T	p.Ile1269Ile	synonymous_variant	30/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3837C>T	p.Ile1279Ile	synonymous_variant	29/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3837C>T	p.Ile1279Ile	synonymous_variant	29/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3837C>T	p.Ile1279Ile	synonymous_variant	29/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3837C>T	p.Ile1279Ile	synonymous_variant	29/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3822C>T	p.Ile1274Ile	synonymous_variant	30/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3807C>T	p.Ile1269Ile	synonymous_variant	30/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3822C>T	p.Ile1274Ile	synonymous_variant	30/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3738C>T	p.Ile1246Ile	synonymous_variant	29/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3747C>T	p.Ile1249Ile	synonymous_variant	29/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2354C>T		non_coding_transcript_exon_variant	27/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2354C>T		3_prime_UTR_variant	27/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152144 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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

GnomAD3 exomes AF: 0.000108 AC: 27 AN: 250148 Hom.: 0 AF XY: 0.0000885 AC XY: 12 AN XY: 135586

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.0000290

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461084 Hom.: 0 Cov.: 29 AF XY: 0.0000289 AC XY: 21 AN XY: 726948

Gnomad4 AFR exome AF: 0.00117

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152262 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74440

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000261

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

Alfa AF: 0.000288 Hom.: 0

Bravo AF: 0.000363

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 14, 2016

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 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	-0.23
CADD	Benign	9.5
DANN	Benign	0.80

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: rs370576211; hg19: chr12-2721098; COSMIC: COSV59715215; COSMIC: COSV59715215;