12-2512935-C-T

Position:

• chr12-2512935-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000719.7(CACNA1C):​c.1341C>T​(p.Ile447Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,218 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 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.75

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-2512935-C-T is Benign according to our data. Variant chr12-2512935-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282043.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.75 with no splicing effect.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1431C>T	p.Ile477Ile	synonymous_variant	9/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1341C>T	p.Ile447Ile	synonymous_variant	9/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1431C>T	p.Ile477Ile	synonymous_variant	9/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1341C>T	p.Ile447Ile	synonymous_variant	9/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1341C>T	p.Ile447Ile	synonymous_variant	9/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1341C>T	p.Ile447Ile	synonymous_variant	9/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1431C>T	p.Ile477Ile	synonymous_variant	9/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1431C>T	p.Ile477Ile	synonymous_variant	9/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1431C>T	p.Ile477Ile	synonymous_variant	9/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1431C>T	p.Ile477Ile	synonymous_variant	9/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1341C>T	p.Ile447Ile	synonymous_variant	9/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1341C>T	p.Ile447Ile	synonymous_variant	9/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1332C>T	p.Ile444Ile	synonymous_variant	9/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1341C>T	p.Ile447Ile	synonymous_variant	9/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19549C>T		intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000450 AC: 11 AN: 244336 Hom.: 0 AF XY: 0.0000453 AC XY: 6 AN XY: 132394

Gnomad AFR exome AF: 0.000404

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000337

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1459084 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 725514

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74326

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00

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: 0.0000986 Hom.: 0

Bravo AF: 0.000106

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 30, 2015

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 18, 2018

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	-0.46
CADD	Benign	3.2
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: rs377643814; hg19: chr12-2622101;