rs1247249384

chr2-219281768-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006736.6(DNAJB2):c.226A>C(p.Thr76Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: DNAJB2 NM_006736.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.26

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15139365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB2	NM_006736.6	c.226A>C	p.Thr76Pro	missense_variant	4/9	ENST00000336576.10
DNAJB2	NM_001039550.2	c.226A>C	p.Thr76Pro	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB2	ENST00000336576.10	c.226A>C	p.Thr76Pro	missense_variant	4/9	1	NM_006736.6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461764 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727176

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: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000284 Hom.: 0

Bravo AF: 0.0000189

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 14, 2021

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Neuronopathy, distal hereditary motor, autosomal recessive 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 07, 2022

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 76 of the DNAJB2 protein (p.Thr76Pro). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with DNAJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 540530). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.037	T;T;.;T;T;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.45	T;T;T;T;T;T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.49	N;.;N;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T;T
Polyphen		0.025	B;.;B;.;.;.;.
Vest4		0.21
MutPred		0.27		Loss of catalytic residue at T76 (P = 0.0059);Loss of catalytic residue at T76 (P = 0.0059);Loss of catalytic residue at T76 (P = 0.0059);Loss of catalytic residue at T76 (P = 0.0059);Loss of catalytic residue at T76 (P = 0.0059);Loss of catalytic residue at T76 (P = 0.0059);Loss of catalytic residue at T76 (P = 0.0059);
MVP		0.55
MPC		0.29
ClinPred		0.13	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.42

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

Other links and lift over

dbSNP: rs1247249384; hg19: chr2-220146490;