rs369661561

Positions:

chr2-219281937-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_StrongPM2PP3_StrongPP5

The NM_006736.6(DNAJB2):c.230-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000613 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DNAJB2
NM_006736.6 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2O:1

Conservation

PhyloP100: 6.29

Variant links:

Genes affected

DNAJB2 (HGNC:5228): (DnaJ heat shock protein family (Hsp40) member B2) This gene is almost exclusively expressed in the brain, mainly in the neuronal layers. It encodes a protein that shows sequence similarity to bacterial DnaJ protein and the yeast homologs. In bacteria, this protein is implicated in protein folding and protein complex dissociation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2011]

DNAJB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12512821 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 2-219281937-A-G is Pathogenic according to our data. Variant chr2-219281937-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234675.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB2	NM_006736.6 linkuse as main transcript	c.230-2A>G		splice_acceptor_variant		ENST00000336576.10
DNAJB2	NM_001039550.2 linkuse as main transcript	c.230-2A>G		splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB2	ENST00000336576.10 linkuse as main transcript	c.230-2A>G		splice_acceptor_variant		1	NM_006736.6		P25686-3

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152166

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251262

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000547

AC:

AN:

1461746

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727174

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:

0.0000562

Gnomad4 NFE exome

AF:

0.0000665

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000125

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000173

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 17, 2020	PVS1, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 2022	Identified in an individual from a cohort with suspected Charcot-Marie-Tooth disease, however, it is unclear if this individual harbored a second DNAJB2 variant and clinical information was not provided (Volodarsky et al., 2021); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25274842, 22522442, 32376792) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -

Neuronopathy, distal hereditary motor, autosomal recessive 5

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 18, 2023

This sequence change affects an acceptor splice site in intron 4 of the DNAJB2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAJB2 are known to be pathogenic (PMID: 22522442, 25274842). This variant is present in population databases (rs369661561, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with clinical features of Charcot-Marie-Tooth disease (PMID: 32376792). ClinVar contains an entry for this variant (Variation ID: 234675). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 2020

The c.230-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the DNAJB2 gene. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The exact functional effect of the missing amino acids is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Charcot-Marie-Tooth disease type 2;C4749918:Neuronopathy, distal hereditary motor, autosomal recessive 5

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Likely pathogenic and reported on 11-23-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D

GERP RS

4.5

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.62

Position offset: 23

DS_AL_spliceai

1.0

Position offset: 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