3-53702771-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS1_Supporting

The NM_001128840.3(CACNA1D):c.1351G>C(p.Glu451Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,614,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

CACNA1D
NM_001128840.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 9.96

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 Uncertain_significance. Variant got 0 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.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000177 (27/152378) while in subpopulation NFE AF= 0.000368 (25/68024). AF 95% confidence interval is 0.000255. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 9 of 49	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 9 of 48	ENST00000350061.11	NP_001122312.1	Q01668-1Q59GD8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 9 of 49	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 link	c.1351G>C	p.Glu451Gln	missense_variant	Exon 9 of 48	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000367

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

251450

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000276

AC:

403

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000253

AC XY:

184

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000348

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000177

AC:

AN:

152378

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000346

Hom.:

Bravo

AF:

0.000166

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 451 of the CACNA1D protein (p.Glu451Gln). This variant is present in population databases (rs200910800, gnomAD 0.03%). 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: 228464). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1D protein function with a negative predictive value of 80%. 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. -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CACNA1D p.Glu451Gln variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs200910800), LOVD 3.0 and ClinVar (classified as a VUS by Laboratory for Molecular Medicine). The variant was identified in control databases in 42 of 282848 chromosomes at a frequency of 0.000148 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 39 of 129154 chromosomes (freq: 0.000302), Other in 1 of 7222 chromosomes (freq: 0.000139) and African in 2 of 24972 chromosomes (freq: 0.00008), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Glu451 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Aug 24, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Jul 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu451Gln variant in CACNA1D has not been previously reported in individua ls with hearing loss, but has been identified in 12/66694 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200910800). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational predi ction tools and conservation analysis do not provide strong support for or again st an impact to the protein. In summary, the clinical significance of the p.Glu4 51Gln variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Jul 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1351G>C (p.E451Q) alteration is located in exon 9 (coding exon 9) of the CACNA1D gene. This alteration results from a G to C substitution at nucleotide position 1351, causing the glutamic acid (E) at amino acid position 451 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.068

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.46

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

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.061

MetaRNN

Uncertain

0.47

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

MetaSVM

Uncertain

0.47

MutationAssessor

Uncertain

2.6

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

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.5

.;N;.;.;D;D;.;.;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.021

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

Sift4G

Benign

0.070

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

Polyphen

0.60, 0.99, 0.95

.;P;.;D;D;.;.;.;P

Vest4

0.45, 0.52, 0.48

MVP

0.92

MPC

1.7

ClinPred

0.16

GERP RS

4.5

Varity_R

0.18

gMVP

0.26

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