rs3821039

Variant names:

• chr2-219283125-G-A
• rs3821039
• NM_006736.6:c.446-8G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:5
• Conservation: PhyloP100: -1.90
• Publications: 6 publications found

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: Orphanet, ClinGen
• neuronopathy, distal hereditary motor, autosomal recessive 5

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006736.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB2	NM_006736.6	MANE Select	c.446-8G>A		splice_region intron	N/A	NP_006727.2
	DNAJB2	NM_001039550.2		c.446-8G>A		splice_region intron	N/A	NP_001034639.1	P25686-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB2	ENST00000336576.10	TSL:1 MANE Select	c.446-8G>A		splice_region intron	N/A	ENSP00000338019.5	P25686-3
	DNAJB2	ENST00000933785.1		c.446-8G>A		splice_region intron	N/A	ENSP00000603844.1
	DNAJB2	ENST00000392086.8	TSL:2	c.446-8G>A		splice_region intron	N/A	ENSP00000375936.4	P25686-2

Frequencies

GnomAD3 genomes AF: 0.0959 AC: 14581 AN: 152078 Hom.: 1684 Cov.: 32

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

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.: 32 AF XY: 0.0264 AC XY: 19199 AN XY: 727186

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

GnomAD4 genome AF: 0.0962 AC: 14634 AN: 152196 Hom.: 1698 Cov.: 32 AF XY: 0.0935 AC XY: 6961 AN XY: 74418

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: 51 AN: 4826

European-Finnish (FIN) AF: 0.0175 AC: 186 AN: 10606

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0188 AC: 1282 AN: 68016

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal recessive 5 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.50
DANN	Benign	0.88
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3821039; hg19: chr2-220147847; COSMIC: COSV60678154; COSMIC: COSV60678154;