rs750835120

Positions:

• chr12-2688752-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000719.7(CACNA1C):​c.6090C>T​(p.His2030His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,572,968 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.77

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-2688752-C-T is Benign according to our data. Variant chr12-2688752-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238177.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6090C>T	p.His2030His	synonymous_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6090C>T	p.His2030His	synonymous_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6090C>T	p.His2030His	synonymous_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6090C>T	p.His2030His	synonymous_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6429C>T	p.His2143His	synonymous_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6303C>T	p.His2101His	synonymous_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6270C>T	p.His2090His	synonymous_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6255C>T	p.His2085His	synonymous_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6234C>T	p.His2078His	synonymous_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6213C>T	p.His2071His	synonymous_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6195C>T	p.His2065His	synonymous_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6195C>T	p.His2065His	synonymous_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6180C>T	p.His2060His	synonymous_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6180C>T	p.His2060His	synonymous_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6180C>T	p.His2060His	synonymous_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6180C>T	p.His2060His	synonymous_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6174C>T	p.His2058His	synonymous_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6165C>T	p.His2055His	synonymous_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6150C>T	p.His2050His	synonymous_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6147C>T	p.His2049His	synonymous_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6147C>T	p.His2049His	synonymous_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6147C>T	p.His2049His	synonymous_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6141C>T	p.His2047His	synonymous_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6132C>T	p.His2044His	synonymous_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6114C>T	p.His2038His	synonymous_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6114C>T	p.His2038His	synonymous_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6108C>T	p.His2036His	synonymous_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6090C>T	p.His2030His	synonymous_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6090C>T	p.His2030His	synonymous_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6090C>T	p.His2030His	synonymous_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6090C>T	p.His2030His	synonymous_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6090C>T	p.His2030His	synonymous_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6081C>T	p.His2027His	synonymous_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6057C>T	p.His2019His	synonymous_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000152 AC: 3 AN: 197806 Hom.: 0 AF XY: 0.0000185 AC XY: 2 AN XY: 108316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000401

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000352 AC: 50 AN: 1420774 Hom.: 0 Cov.: 33 AF XY: 0.0000327 AC XY: 23 AN XY: 702720

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000734

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000385

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000786 Hom.: 0

Bravo AF: 0.0000189

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)

Sep 25, 2015

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 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	-0.67
CADD	Benign	5.1
DANN	Benign	0.87

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: rs750835120; hg19: chr12-2797918; COSMIC: COSV59772378; COSMIC: COSV59772378;