2-219279897-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006736.6(DNAJB2):c.64G>C(p.Ala22Pro) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A22E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAJB2 NM_006736.6 missense, splice_region
• Scores: Splicing: ADA: 0.9906
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.01

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 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. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB2	NM_006736.6	c.64G>C	p.Ala22Pro	missense_variant, splice_region_variant	2/9	ENST00000336576.10
DNAJB2	NM_001039550.2	c.64G>C	p.Ala22Pro	missense_variant, splice_region_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB2	ENST00000336576.10	c.64G>C	p.Ala22Pro	missense_variant, splice_region_variant	2/9	1	NM_006736.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2021

The p.A22P variant (also known as c.64G>C), located in coding exon 1 of the DNAJB2 gene, results from a G to C substitution at nucleotide position 64. The alanine at codon 22 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T;.;T;T;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.054	D
MutationAssessor	Pathogenic	4.3	H;.;H;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D
Polyphen		0.64	P;.;B;.;.;.;.
Vest4		0.92
MutPred		0.82		Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);Gain of disorder (P = 0.0573);
MVP		0.47
MPC		0.42
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220144619;