rs200382504

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS1

The NM_001128840.3(CACNA1D):c.3821C>T(p.Ser1274Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000331 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 0 hom. )

Consequence

CACNA1D
NM_001128840.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 3.94

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 -6 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=0.097922385).

BP6

Variant 3-53762032-C-T is Benign according to our data. Variant chr3-53762032-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228465.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000184 (28/152214) while in subpopulation NFE AF= 0.000294 (20/68028). AF 95% confidence interval is 0.000194. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1D	NM_000720.4 link	c.3881C>T	p.Ser1294Phe	missense_variant	Exon 31 of 49	ENST00000288139.11	NP_000711.1	Q01668-2Q59GD8
CACNA1D	NM_001128840.3 link	c.3821C>T	p.Ser1274Phe	missense_variant	Exon 30 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.3881C>T	p.Ser1294Phe	missense_variant	Exon 31 of 49	1	NM_000720.4	ENSP00000288139.3		Q01668-2
CACNA1D	ENST00000350061.11 link	c.3821C>T	p.Ser1274Phe	missense_variant	Exon 30 of 48	1	NM_001128840.3	ENSP00000288133.5		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000231

AC:

AN:

251496

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000346

AC:

506

AN:

1461536

Hom.:

Cov.:

AF XY:

0.000359

AC XY:

261

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.000612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000386

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000184

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000409

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2025	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Dec 05, 2022	The p.Ser1294Phe variant in the CACNA1D gene has not been previously reported in association with disease. This variant has been identified in 36/129196 European Non-Finnish chromosomes (63/282888 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 228465). The CACNA1D gene has fewer missense variants in the general population than expected. A low rate of missense variation may suggest that this gene is intolerant to missense variation. Computational tools predict that this variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ser1294Phe variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP2; PP3] -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 01, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Ser1294Phe va riant in CACNA1D has been previously reported by our laboratory in one individua l with an alternate genetic etiology to explain the hearing loss. This variant was identified in 16/66738 European chromosomes by the Exome Aggregation Consort ium (ExAC, http://exac.broadinstitute.org; dbSNP rs200382504); however, this fre quency in the general population is not high enough to rule out a pathogenic rol e. Computational prediction tools and conservation analyses suggest that this va riant may not impact the protein, though this information is not predictive enou gh to rule out pathogenicity. In summary, while the clinical significance of the p.Ser1294Phe 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

Mar 19, 2021

The c.3881C>T (p.S1294F) alteration is located in exon 31 (coding exon 31) of the CACNA1D gene. This alteration results from a C to T substitution at nucleotide position 3881, causing the serine (S) at amino acid position 1294 to be replaced by a phenylalanine (F). The in silico prediction for the p.S1294F alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CACNA1D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2022

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

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Benign

0.31

DEOGEN2

Uncertain

0.53

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

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.090

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.066

MetaRNN

Benign

0.098

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

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

-1.9

.;N;.;.;.;N;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.3

.;N;.;.;N;N;.;.

REVEL

Uncertain

0.51

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0, 0.010

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

Vest4

0.52, 0.53, 0.53

MVP

0.88

MPC

1.6

ClinPred

0.083

GERP RS

5.4

Varity_R

0.16

gMVP

0.79

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