rs28377945

Positions:

• chr7-157366482-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_058246.4(DNAJB6):​c.176-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,612,064 control chromosomes in the GnomAD database, including 1,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (222 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1273 hom.)
• Consequence: DNAJB6 NM_058246.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.66

Genes affected

DNAJB6 (HGNC:14888): (DnaJ heat shock protein family (Hsp40) member B6) This gene encodes a member of the DNAJ protein family. DNAJ family members are characterized by a highly conserved amino acid stretch called the 'J-domain' and function as one of the two major classes of molecular chaperones involved in a wide range of cellular events, such as protein folding and oligomeric protein complex assembly. This family member may also play a role in polyglutamine aggregation in specific neurons. Alternative splicing of this gene results in multiple transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

DNAJB6 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-157366482-A-G is Benign according to our data. Variant chr7-157366482-A-G is described in ClinVar as [Benign]. Clinvar id is 262305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-157366482-A-G is described in Lovd as [Benign]. Variant chr7-157366482-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.176-20A>G		intron_variant		ENST00000262177.9	NP_490647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJB6	ENST00000262177.9	c.176-20A>G		intron_variant		1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7522 AN: 152152 Hom.: 220 Cov.: 33

Gnomad AFR AF: 0.0802

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0493

GnomAD3 exomes AF: 0.0365 AC: 9154 AN: 251076 Hom.: 230 AF XY: 0.0361 AC XY: 4902 AN XY: 135694

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.0145

Gnomad SAS exome AF: 0.0307

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0395

GnomAD4 exome AF: 0.0391 AC: 57150 AN: 1459794 Hom.: 1273 Cov.: 30 AF XY: 0.0387 AC XY: 28098 AN XY: 726308

Gnomad4 AFR exome AF: 0.0786

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.0141

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.0301

Gnomad4 FIN exome AF: 0.0430

Gnomad4 NFE exome AF: 0.0409

Gnomad4 OTH exome AF: 0.0377

GnomAD4 genome AF: 0.0495 AC: 7532 AN: 152270 Hom.: 222 Cov.: 33 AF XY: 0.0483 AC XY: 3598 AN XY: 74442

Gnomad4 AFR AF: 0.0802

Gnomad4 AMR AF: 0.0320

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.0418

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0415 Hom.: 26

Bravo AF: 0.0493

Asia WGS AF: 0.0340 AC: 119 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs28377945; hg19: chr7-157159176; COSMIC: COSV51100899; COSMIC: COSV51100899;