chr3-53740333-G-C

Position:

chr3-53740333-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS1

The NM_000720.4(CACNA1D):c.2865G>C(p.Leu955=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00047 in 1,607,828 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

CACNA1D
NM_000720.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.84

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 3-53740333-G-C is Benign according to our data. Variant chr3-53740333-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 501392.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr3-53740333-G-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.84 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000991 (151/152308) while in subpopulation AFR AF= 0.00207 (86/41556). AF 95% confidence interval is 0.00172. There are 0 homozygotes in gnomad4. There are 73 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.2865G>C	p.Leu955=	synonymous_variant	22/49	ENST00000288139.11	NP_000711.1
CACNA1D	NM_001128840.3 linkuse as main transcript	c.2805G>C	p.Leu935=	synonymous_variant	21/48	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.2865G>C	p.Leu955=	synonymous_variant	22/49	1	NM_000720.4	ENSP00000288139	P2	Q01668-2
CACNA1D	ENST00000350061.11 linkuse as main transcript	c.2805G>C	p.Leu935=	synonymous_variant	21/48	1	NM_001128840.3	ENSP00000288133		Q01668-1

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000668

AC:

168

AN:

251420

Hom.:

AF XY:

0.000640

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.000378

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000415

AC:

604

AN:

1455520

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

290

AN XY:

724710

show subpopulations

Gnomad4 AFR exome

AF:

0.00195

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00441

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000468

Gnomad4 NFE exome

AF:

0.000272

Gnomad4 OTH exome

AF:

0.000948

GnomAD4 genome

AF:

0.000991

AC:

151

AN:

152308

Hom.:

Cov.:

AF XY:

0.000980

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.000915

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000916

Hom.:

Bravo

AF:

0.00107

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 21, 2017	p.Leu955Leu in exon 22 of CACNA1D: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 0.23% (55/24024 ) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnom ad.broadinstitute.org/; dbSNP rs150266932). ACMG/AMP criteria applied: BS1, BP7. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.2

DANN

Benign

0.81

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