2-219284676-G-C

Variant names:

• chr2-219284676-G-C
• NM_006736.6:c.664G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_006736.6(DNAJB2):​c.664G>C​(p.Glu222Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJB2 NM_006736.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.31

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.

• PM1: In a mutagenesis_site Loss of interaction with polyubiquitin chains, loss of interaction with PSMA3, and loss of the ability to protect ATXN3 from proteasomal degradation; when associated with A-219; A-262 and A-265. (size 0) in uniprot entity DNJB2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29611337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB2	NM_006736.6	c.664G>C	p.Glu222Gln	missense_variant	Exon 9 of 9	ENST00000336576.10	NP_006727.2
DNAJB2	NM_001039550.2	c.664G>C	p.Glu222Gln	missense_variant	Exon 9 of 10		NP_001034639.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB2	ENST00000336576.10	c.664G>C	p.Glu222Gln	missense_variant	Exon 9 of 9	1	NM_006736.6	ENSP00000338019.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723244

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;.;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.98	D;.;D;.
Vest4		0.25
MutPred		0.18		Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);.;
MVP		0.31
MPC		0.84
ClinPred		0.89	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-220149398;