rs115066564

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2

The NM_000720.4(CACNA1D):c.2789G>A(p.Arg930His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000732 in 1,613,812 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R930C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 3 hom. )

Consequence

CACNA1D
NM_000720.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 10.0

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

aldosterone-producing adenoma with seizures and neurological abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
sinoatrial node dysfunction and deafness
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

CACNA1D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.20425305).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0004 (61/152318) while in subpopulation SAS AF = 0.00145 (7/4830). AF 95% confidence interval is 0.000679. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.2789G>A	p.Arg930His	missense_variant	Exon 21 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3 link	c.2729G>A	p.Arg910His	missense_variant	Exon 20 of 48	ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 link	c.2789G>A	p.Arg930His	missense_variant	Exon 21 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11 link	c.2729G>A	p.Arg910His	missense_variant	Exon 20 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000462

AC:

116

AN:

251006

AF XY:

0.000575

show subpopulations

Gnomad AFR exome

AF:

0.000310

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000476

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000766

AC:

1120

AN:

1461494

Hom.:

Cov.:

AF XY:

0.000761

AC XY:

553

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.000313

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000835

AC:

928

AN:

1111830

Other (OTH)

AF:

0.000547

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000400

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41572

American (AMR)

AF:

0.000457

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000551

Hom.:

Bravo

AF:

0.000431

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Jan 07, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 07, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Arg930His var iant in CACNA1D has been identified by our laboratory in one individual with hea ring loss and has been identified in 0.1% (40/30780) of South Asian chromosomes including one homozygotes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNP rs115066564). Computational prediction tools and c onservation analyses suggest that this variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, while the clinical significance of the p.Arg930His variant is uncertain, its fre quency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting, PP3.

not provided

Uncertain:1Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 04, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32561571, 36430690, 37025382, 37217689)

Inborn genetic diseases

Uncertain:1

Sep 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Unlikely to be causative of Primary aldosteronism, seizures, and neurologic abnormalities (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

CACNA1D-related disorder

Benign:1

Sep 05, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.22

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0

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

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.20

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;M;.;.;.;M;.;.;.

PhyloP100

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.0

ClinPred

0.092

GERP RS

5.5

Varity_R

0.32

gMVP

0.76

Mutation Taster

=76/24

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over