chr2-219283125-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006736.6(DNAJB2):c.446-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0343 in 1,613,938 control chromosomes in the GnomAD database, including 3,924 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 Benign (★★).

Frequency

Genomes: 𝑓 0.096 ( 1698 hom., cov: 32)

Exomes 𝑓: 0.028 ( 2226 hom. )

Consequence

DNAJB2
NM_006736.6 splice_region, intron

Scores

Splicing: ADA: 0.0002655

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.90

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease axonal type 2T
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
neuronopathy, distal hereditary motor, autosomal recessive 5
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

DNAJB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 2-219283125-G-A is Benign according to our data. Variant chr2-219283125-G-A is described in ClinVar as Benign. ClinVar VariationId is 473303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB2	NM_006736.6 link	c.446-8G>A		splice_region_variant, intron_variant	Intron 6 of 8	ENST00000336576.10	NP_006727.2
DNAJB2	NM_001039550.2 link	c.446-8G>A		splice_region_variant, intron_variant	Intron 6 of 9		NP_001034639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB2	ENST00000336576.10 link	c.446-8G>A		splice_region_variant, intron_variant	Intron 6 of 8	1	NM_006736.6	ENSP00000338019.5

Frequencies

GnomAD3 genomes

AF:

0.0959

AC:

14581

AN:

152078

Hom.:

1684

Cov.:

show subpopulations

Gnomad AFR

AF:

0.277

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.0424

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.0175

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0783

GnomAD2 exomes

AF:

0.0446

AC:

11194

AN:

251040

AF XY:

0.0387

show subpopulations

Gnomad AFR exome

AF:

0.281

Gnomad AMR exome

AF:

0.0238

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.0192

Gnomad NFE exome

AF:

0.0200

Gnomad OTH exome

AF:

0.0375

GnomAD4 exome

AF:

0.0279

AC:

40800

AN:

1461742

Hom.:

2226

Cov.:

AF XY:

0.0264

AC XY:

19199

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.284

AC:

9499

AN:

33474

American (AMR)

AF:

0.0264

AC:

1179

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0312

AC:

815

AN:

26132

East Asian (EAS)

AF:

0.147

AC:

5836

AN:

39696

South Asian (SAS)

AF:

0.00863

AC:

744

AN:

86248

European-Finnish (FIN)

AF:

0.0178

AC:

951

AN:

53410

Middle Eastern (MID)

AF:

0.0439

AC:

253

AN:

5768

European-Non Finnish (NFE)

AF:

0.0169

AC:

18825

AN:

1111906

Other (OTH)

AF:

0.0447

AC:

2698

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

2250

4500

6749

8999

11249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

878

1756

2634

3512

4390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0962

AC:

14634

AN:

152196

Hom.:

1698

Cov.:

AF XY:

0.0935

AC XY:

6961

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.277

AC:

11513

AN:

41502

American (AMR)

AF:

0.0423

AC:

647

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3472

East Asian (EAS)

AF:

0.127

AC:

655

AN:

5166

South Asian (SAS)

AF:

0.0106

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0175

AC:

186

AN:

10606

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0188

AC:

1282

AN:

68016

Other (OTH)

AF:

0.0789

AC:

167

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

563

1126

1688

2251

2814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0503

Hom.:

530

Bravo

AF:

0.107

Asia WGS

AF:

0.0780

AC:

269

AN:

3478

EpiCase

AF:

0.0194

EpiControl

AF:

0.0184

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal recessive 5

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.50

(source)

DANN

Benign

0.88

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.14

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over