rs193270389

Positions:

chr3-53731151-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000720.4(CACNA1D):c.2466+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,593,266 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 1 hom. )

Consequence

CACNA1D
NM_000720.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.3392

Clinical Significance

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

Conservation

PhyloP100: -0.309

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 3-53731151-G-A is Benign according to our data. Variant chr3-53731151-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-53731151-G-A is described in Lovd as [Benign]. Variant chr3-53731151-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000184 (28/152322) while in subpopulation EAS AF= 0.00464 (24/5176). AF 95% confidence interval is 0.0032. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1D	NM_000720.4 linkuse as main transcript	c.2466+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3 linkuse as main transcript	c.2406+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000350061.11	NP_001122312.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1D	ENST00000288139.11 linkuse as main transcript	c.2466+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000720.4	ENSP00000288139	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.2406+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001128840.3	ENSP00000288133		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152204

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:

0.00463

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000322

AC:

AN:

251176

Hom.:

AF XY:

0.000287

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00413

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000895

AC:

129

AN:

1440944

Hom.:

Cov.:

AF XY:

0.0000919

AC XY:

AN XY:

718406

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00250

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000366

Gnomad4 OTH exome

AF:

0.000268

GnomAD4 genome

AF:

0.000184

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00464

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000497

Hom.:

Bravo

AF:

0.000136

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 01, 2016	c.2466+5G>A in intron 18 of CACNA1D: This variant is not expected to have clini cal significance because it has been identified in 0.4% (30/8554) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs193270389). -

CACNA1D-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2020

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.1

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.34

dbscSNV1_RF

Benign

0.37

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