rs781171340

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000720.4(CACNA1D):c.3922G>A(p.Glu1308Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,610,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CACNA1D
NM_000720.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.38

Publications

3 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.3922G>A	p.Glu1308Lys	missense_variant	Exon 31 of 49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3 link	c.3862G>A	p.Glu1288Lys	missense_variant	Exon 30 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.3922G>A	p.Glu1308Lys	missense_variant	Exon 31 of 49	1	NM_000720.4	ENSP00000288139.3
CACNA1D	ENST00000350061.11 link	c.3862G>A	p.Glu1288Lys	missense_variant	Exon 30 of 48	1	NM_001128840.3	ENSP00000288133.5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152246

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251458

AF XY:

0.0000221

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1458024

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725610

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86150

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000902

AC:

AN:

1108530

Other (OTH)

AF:

0.00

AC:

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74500

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000354

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Glu1308Lys variant in CACNA1D has not been previously reported in individu als with hearing loss, but has been identified in 3/16504 of South Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs781171340). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Glu1308Lys variant is uncertain. -

not provided

Uncertain:1

May 13, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This sequence change replaces glutamic acid with lysine at codon 1308 of the CACNA1D protein (p.Glu1308Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs781171340, ExAC 0.02%). This variant has not been reported in the literature in individuals with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 504961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

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

PhyloP100

4.4

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.81

Sift

Benign

0.064

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

Sift4G

Benign

0.070

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

Polyphen

0.97, 1.0

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

Vest4

0.75, 0.73, 0.75

MutPred

0.69

.;Gain of ubiquitination at E1288 (P = 0.0128);Gain of ubiquitination at E1288 (P = 0.0128);.;.;Gain of ubiquitination at E1288 (P = 0.0128);Gain of ubiquitination at E1288 (P = 0.0128);.;

MVP

0.85

MPC

1.1

ClinPred

0.83

GERP RS

4.6

Varity_R

0.45

gMVP

0.91

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over