3-53702809-T-G

Position:

chr3-53702809-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate

The NM_001128840.3(CACNA1D):c.1389T>G(p.Asn463Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CACNA1D
NM_001128840.3 missense, splice_region

Scores

Splicing: ADA: 0.0001841

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.238

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 Likely_benign. Variant got -1 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 6.6073 (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=0.21469611).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.1389T>G	p.Asn463Lys	missense_variant, splice_region_variant	9/49	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 linkuse as main transcript	c.1389T>G	p.Asn463Lys	missense_variant, splice_region_variant	9/48	ENST00000350061.11	NP_001122312.1	Q01668-1Q59GD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.1389T>G	p.Asn463Lys	missense_variant, splice_region_variant	9/49	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.1389T>G	p.Asn463Lys	missense_variant, splice_region_variant	9/48	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251318

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000211

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000177

AC:

259

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

129

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000217

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 463 of the CACNA1D protein (p.Asn463Lys). This variant is present in population databases (rs150652713, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 504802). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 06, 2017

The p.Asn463Lys variant in CACNA1D has not been previously reported in individua ls with hearing loss, but has been identified in 29/126606 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; db SNP rs150652713). This variant is located in the last three bases of the exon, w hich is part of the 5? splice region; however computational tools do not predict altered splicing. Computational prediction tools and conservation analysis sugg est that the amino acid change may not impact the protein. However, these tools are not predictive enough to rule out pathogenicity. In summary, the clinical si gnificance of the p.Asn463Lys variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Uncertain

0.49

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

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.86

D;D;D;.;D;D;D;D;D;T

M_CAP

Benign

0.076

MetaRNN

Benign

0.21

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

MetaSVM

Benign

-0.53

MutationAssessor

Benign

1.0

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

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-4.3

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

REVEL

Uncertain

0.34

Sift

Benign

0.36

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

Sift4G

Benign

0.89

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

Polyphen

0.0060, 0.071, 0.0040

.;B;.;B;B;.;.;.;B;.

Vest4

0.55, 0.68, 0.55

MutPred

0.38

.;Gain of ubiquitination at N463 (P = 0.0039);Gain of ubiquitination at N463 (P = 0.0039);Gain of ubiquitination at N463 (P = 0.0039);Gain of ubiquitination at N463 (P = 0.0039);Gain of ubiquitination at N463 (P = 0.0039);Gain of ubiquitination at N463 (P = 0.0039);.;.;.;

MVP

0.69

MPC

1.2

ClinPred

0.14

GERP RS

-7.5

Varity_R

0.34

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.17

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