rs145109446

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000722.4(CACNA2D1):c.2751A>T(p.Gln917His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,612,256 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

CACNA2D1
NM_000722.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0500

Variant links:

Genes affected

CACNA2D1 (HGNC:1399): (calcium voltage-gated channel auxiliary subunit alpha2delta 1) The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

CACNA2D1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052798003).

BP6

Variant 7-81964085-T-A is Benign according to our data. Variant chr7-81964085-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 580176.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr7-81964085-T-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA2D1	NM_000722.4 link	c.2751A>T	p.Gln917His	missense_variant	34/39	ENST00000356860.8	NP_000713.2	P54289-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA2D1	ENST00000356860.8 link	c.2751A>T	p.Gln917His	missense_variant	34/39	1	NM_000722.4	ENSP00000349320.3		P54289-2

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000353

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000128

AC:

AN:

249130

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

134972

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000267

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1460194

Hom.:

Cov.:

AF XY:

0.000190

AC XY:

138

AN XY:

726422

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000261

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.000178

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000353

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2023

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 917 of the CACNA2D1 protein (p.Gln917His). This variant is present in population databases (rs145109446, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 20817017). ClinVar contains an entry for this variant (Variation ID: 580176). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2020

This variant is associated with the following publications: (PMID: 27711072, 20817017, 23414114, 25527503, 30821013) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2020

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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.048

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.036

MetaRNN

Benign

0.053

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.69

.;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.58

N;N

REVEL

Benign

0.13

Sift

Benign

0.14

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0

B;.

Vest4

0.20

MVP

0.19

MPC

0.43

ClinPred

0.049

GERP RS

-2.6

Varity_R

0.059

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over