rs148898845

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_000720.4(CACNA1D):c.5075G>A(p.Arg1692Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,459,578 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000026 ( 1 hom. )

Consequence

CACNA1D
NM_000720.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.60

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 -4 ACMG points.

PP2

Missense variant where missense usually causes diseases, CACNA1D

BP4

Computational evidence support a benign effect (MetaRNN=0.059493244).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000026 (38/1459578) while in subpopulation MID AF= 0.00295 (17/5766). AF 95% confidence interval is 0.00188. There are 1 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.5075G>A	p.Arg1692Gln	missense_variant	42/49	ENST00000288139.11
CACNA1D	NM_001128840.3 linkuse as main transcript	c.5015G>A	p.Arg1672Gln	missense_variant	41/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.5075G>A	p.Arg1692Gln	missense_variant	42/49	1	NM_000720.4	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.5015G>A	p.Arg1672Gln	missense_variant	41/48	1	NM_001128840.3		Q01668-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251486

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1459578

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000901

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Arg1692Gln va riant in CACNA1D has not been previously reported in individuals with hearing lo ss, but has been identified in 1/16512 South Asian chromosomes and 1/11576 Latin o chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs148898845). Arginine (Arg) at position 1692 is not conserved in mammals or evolutionarily distant species and 2 mammals (opossum and Tasmanian devil) carry a glutamine (Gln) at this position, supporting that this change may be tolerated. In summary, while the clinical significance of the p.Arg1692Gln variant is uncertain, these data suggest that it is more likely to be benign. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.5075G>A (p.R1692Q) alteration is located in exon 42 (coding exon 42) of the CACNA1D gene. This alteration results from a G to A substitution at nucleotide position 5075, causing the arginine (R) at amino acid position 1692 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 04, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 504808). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. This variant is present in population databases (rs148898845, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1692 of the CACNA1D protein (p.Arg1692Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.94

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.87

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

M_CAP

Benign

0.033

MetaRNN

Benign

0.059

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

MetaSVM

Uncertain

-0.089

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

Polyphen

0.0010, 0.029

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

Vest4

0.18, 0.18, 0.19

MVP

0.55

MPC

0.43

ClinPred

0.054

GERP RS

-0.096

Varity_R

0.039

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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