rs770886605

Variant summary

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

The NM_000720.4(CACNA1D):c.5873C>T(p.Pro1958Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,609,166 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1958P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CACNA1D
NM_000720.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.63

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 where missense usually causes diseases, CACNA1D

BP4

Computational evidence support a benign effect (MetaRNN=0.07130602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.5873C>T	p.Pro1958Leu	missense_variant	47/49	ENST00000288139.11
CACNA1D	NM_001128840.3 linkuse as main transcript	c.5813C>T	p.Pro1938Leu	missense_variant	46/48	ENST00000350061.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.5873C>T	p.Pro1958Leu	missense_variant	47/49	1	NM_000720.4	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.5813C>T	p.Pro1938Leu	missense_variant	46/48	1	NM_001128840.3		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000444

AC:

AN:

247672

Hom.:

AF XY:

0.0000298

AC XY:

AN XY:

134276

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000275

AC:

AN:

1456992

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

725040

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 06, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 24, 2023	BP4, PP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1958 of the CACNA1D protein (p.Pro1958Leu). This variant is present in population databases (rs770886605, 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: 505106). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 07, 2020	DNA sequence analysis of the CACNA1D gene demonstrated a sequence change, c.5873C>T, in exon 47 that results in an amino acid change, p.Pro1958Leu. This sequence change does not appear to have been previously described in patients with CACNA1D-related disorders and has has been described in the gnomAD database with a low population frequency of 0.0044% (dbSNP rs770886605). The p.Pro1958Leu change affects a moderately conserved amino acid residue located in a domain of the CACNA1D protein that is not known to be functional. The p.Pro1958Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 20, 2016	p.Pro1958Leu in exon 47 of CACNA1D: This variant is not expected to have clinica l significance due to a lack of conservation across species, including mammals. Of note, 8 mammals have a leucine (Leu) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. This variant has been identified in 1/8586 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /exac.broadinstitute.org; dbSNP rs770886605). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.60

Cadd

Benign

Dann

Benign

0.15

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.014

MetaRNN

Benign

0.071

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

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.34

Polyphen

0.0, 0.011

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

Vest4

0.23, 0.22, 0.23

MutPred

0.14

.;Gain of glycosylation at S1933 (P = 0.0024);.;.;.;.;.;

MVP

0.28

MPC

0.38

ClinPred

0.021

GERP RS

3.9

Varity_R

0.027

gMVP

0.37

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.

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