Genetic Variant NM_006736.6:c.65C>T (chr2-219279898-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006736.6(DNAJB2):c.65C>T(p.Ala22Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,662 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DNAJB2
NM_006736.6 missense, splice_region

Scores

Splicing: ADA: 0.9910

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.12

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB2	NM_006736.6 link	c.65C>T	p.Ala22Val	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000336576.10	NP_006727.2	P25686-3
DNAJB2	NM_001039550.2 link	c.65C>T	p.Ala22Val	missense_variant, splice_region_variant	Exon 2 of 10		NP_001034639.1	P25686-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB2	ENST00000336576.10 link	c.65C>T	p.Ala22Val	missense_variant, splice_region_variant	Exon 2 of 9	1	NM_006736.6	ENSP00000338019.5		P25686-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;T;.;T;T;.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.5

H;.;H;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.4

D;D;D;D;D;D;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.022

D;D;D;D;D;D;D

Sift4G

Uncertain

0.050

T;D;D;D;T;D;D

Polyphen

0.91

P;.;B;.;.;.;.

Vest4

0.92

MutPred

0.79

Gain of methylation at K21 (P = 0.0311);Gain of methylation at K21 (P = 0.0311);Gain of methylation at K21 (P = 0.0311);Gain of methylation at K21 (P = 0.0311);Gain of methylation at K21 (P = 0.0311);Gain of methylation at K21 (P = 0.0311);Gain of methylation at K21 (P = 0.0311);

MVP

0.40

MPC

0.30

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.81

SpliceAI score (max)

0.68

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.68

Position offset: -2

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over