rs150838215

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS1

The NM_001128840.3(CACNA1D):​c.6437G>A​(p.Arg2146Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,594,098 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CACNA1D
NM_001128840.3 missense

Scores

19

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.50
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2
Missense variant in the CACNA1D gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 27 curated benign missense variants. Gene score misZ: 4.5817 (above the threshold of 3.09). Trascript score misZ: 6.6073 (above the threshold of 3.09). GenCC associations: The gene is linked to sinoatrial node dysfunction and deafness, aldosterone-producing adenoma with seizures and neurological abnormalities.
BP4
Computational evidence support a benign effect (MetaRNN=0.004864514).
BP6
Variant 3-53811357-G-A is Benign according to our data. Variant chr3-53811357-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (197/152314) while in subpopulation AFR AF= 0.00464 (193/41570). AF 95% confidence interval is 0.00411. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1DNM_000720.4 linkc.6497G>A p.Arg2166Lys missense_variant Exon 49 of 49 ENST00000288139.11 NP_000711.1 Q01668-2Q59GD8
CACNA1DNM_001128840.3 linkc.6437G>A p.Arg2146Lys missense_variant Exon 48 of 48 ENST00000350061.11 NP_001122312.1 Q01668-1Q59GD8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1DENST00000288139.11 linkc.6497G>A p.Arg2166Lys missense_variant Exon 49 of 49 1 NM_000720.4 ENSP00000288139.3 Q01668-2
CACNA1DENST00000350061.11 linkc.6437G>A p.Arg2146Lys missense_variant Exon 48 of 48 1 NM_001128840.3 ENSP00000288133.5 Q01668-1

Frequencies

GnomAD3 genomes
AF:
0.00129
AC:
197
AN:
152196
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00466
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
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:
0.00
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.000382
AC:
92
AN:
240542
Hom.:
1
AF XY:
0.000277
AC XY:
36
AN XY:
129854
show subpopulations
Gnomad AFR exome
AF:
0.00461
Gnomad AMR exome
AF:
0.000423
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:
0.00
Gnomad OTH exome
AF:
0.000690
GnomAD4 exome
AF:
0.000141
AC:
203
AN:
1441784
Hom.:
0
Cov.:
31
AF XY:
0.000109
AC XY:
78
AN XY:
714094
show subpopulations
Gnomad4 AFR exome
AF:
0.00522
Gnomad4 AMR exome
AF:
0.000368
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:
0.00000273
Gnomad4 OTH exome
AF:
0.000202
GnomAD4 genome
AF:
0.00129
AC:
197
AN:
152314
Hom.:
1
Cov.:
32
AF XY:
0.00118
AC XY:
88
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00464
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.000273
Hom.:
0
Bravo
AF:
0.00171
ESP6500AA
AF:
0.00499
AC:
22
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000428
AC:
52

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Nov 24, 2014
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Arg2166Lys in exon 49 of CACNA1D: This variant is not expected to have clinical significance because it has been identified in 0.5% (22/4406) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs150838215). -

Jul 31, 2019
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Sep 28, 2020
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1
Mar 24, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

CACNA1D-related disorder Benign:1
Apr 08, 2021
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
0.075
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.21
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Benign
0.086
.;T;.;.;.;.;.
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.85
T;T;.;T;T;T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.0049
T;T;T;T;T;T;T
MetaSVM
Benign
-0.29
T
MutationAssessor
Benign
0.79
.;N;.;.;.;.;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.3
.;N;.;N;N;.;N
REVEL
Benign
0.23
Sift
Benign
0.16
.;T;.;T;T;.;T
Sift4G
Benign
0.41
.;T;.;T;T;.;T
Polyphen
0.0010, 0.0050, 0.012
.;B;B;B;.;.;B
Vest4
0.081, 0.067, 0.092
MVP
0.64
MPC
0.39
ClinPred
0.019
T
GERP RS
3.8
Varity_R
0.18
gMVP
0.39

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.

Other links and lift over

dbSNP: rs150838215; hg19: chr3-53845384; API