rs730882139

Positions:

• chr2-219281772-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_006736.6(DNAJB2):​c.229+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB2 NM_006736.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2
• Conservation: PhyloP100: 8.72

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.054358974 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 12, new splice context is: gtgGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-219281772-G-A is Pathogenic according to our data. Variant chr2-219281772-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 183041.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-219281772-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB2	NM_006736.6	c.229+1G>A		splice_donor_variant		ENST00000336576.10	NP_006727.2
DNAJB2	NM_001039550.2	c.229+1G>A		splice_donor_variant			NP_001034639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJB2	ENST00000336576.10	c.229+1G>A		splice_donor_variant		1	NM_006736.6	ENSP00000338019

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronopathy, distal hereditary motor, autosomal recessive 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 23, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in retention of intron 4 causing a premature stop codon and introduces a premature termination codon (PMID: 25274842). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 183041). Disruption of this splice site has been observed in individual(s) with clinical features of DNAJB2-related conditions (PMID: 25274842). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 4 of the DNAJB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 04, 2014	- -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Autosomal recessive distal spinal muscular atrophy 2 Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jan 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.51		Position offset: 11
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730882139; hg19: chr2-220146494;