rs35090700

Positions:

chr3-53732076-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS1

The NM_000720.4(CACNA1D):c.2527G>A(p.Val843Met) variant causes a missense change. The variant allele was found at a frequency of 0.000207 in 1,611,562 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 0.00097 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CACNA1D
NM_000720.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 4.93

Variant links:

Genes affected

CACNA1D (HGNC:1391): (calcium voltage-gated channel subunit alpha1 D) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

CACNA1D links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1D. . Gene score misZ 4.5817 (greater than the threshold 3.09). Trascript score misZ 6.6047 (greater than threshold 3.09). GenCC has associacion of gene with sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.

BP4

Computational evidence support a benign effect (MetaRNN=0.017587423).

BP6

Variant 3-53732076-G-A is Benign according to our data. Variant chr3-53732076-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500589.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr3-53732076-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000971 (148/152376) while in subpopulation AFR AF= 0.00337 (140/41592). AF 95% confidence interval is 0.00291. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.2527G>A	p.Val843Met	missense_variant	19/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3 linkuse as main transcript	c.2467G>A	p.Val823Met	missense_variant	18/48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.2527G>A	p.Val843Met	missense_variant	19/49	1	NM_000720.4	ENSP00000288139	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.2467G>A	p.Val823Met	missense_variant	18/48	1	NM_001128840.3	ENSP00000288133		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.000972

AC:

148

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251424

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.000145

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:

0.0000440

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000127

AC:

186

AN:

1459186

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

726172

show subpopulations

Gnomad4 AFR exome

AF:

0.00302

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000523

Gnomad4 OTH exome

AF:

0.000332

GnomAD4 genome

AF:

0.000971

AC:

148

AN:

152376

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.00337

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.00108

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 15, 2018	Variant classified as Uncertain Significance - Favor Benign. The p.Val843Met var iant in CACNA1D has been previously reported by our laboratory in the heterozygo us state in 1 individual with hearing loss. This variant has been identified in 0.25% (59/24036) of African chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org/; dbSNP rs35090700). Computational predicti on tools and conservation analysis suggest that the p.Val843Met variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Val843Met v ariant is uncertain, its frequency and the computational data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2021	DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.2527G>A, in exon 19 that results in an amino acid change, p.Val843Met. This sequence change does not appear to have been previously described in patients with CACNA1D-related disorders and has been described in the gnomAD database with a population frequency of 0.26% in African subpopulation (dbSNP rs35090700). The p.Val843Met change affects a moderately conserved amino acid residue located in a domain of the CACNA1D protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val843Met substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Val843Met change remains unknown at this time. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

CACNA1D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 24, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

.;T;.;.;.;.;.;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D;.;D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.018

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

1.4

.;L;.;.;.;L;.;.;.

MutationTaster

Benign

0.75

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.89

.;N;.;.;N;N;.;.;N

REVEL

Uncertain

0.36

Sift

Benign

0.20

.;T;.;.;T;T;.;.;T

Sift4G

Benign

0.37

.;T;.;.;T;T;.;.;T

Polyphen

0.31, 0.58, 0.89

.;B;.;P;P;.;.;.;P

Vest4

0.42, 0.39, 0.40

MVP

0.77

MPC

1.3

ClinPred

0.030

GERP RS

6.0

Varity_R

0.14

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