rs373070679

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_058246.4(DNAJB6):c.602G>A(p.Arg201Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000812 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R201R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

DNAJB6
NM_058246.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.41

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13091996).

BP6

Variant 7-157384990-G-A is Benign according to our data. Variant chr7-157384990-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286265.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000092 (14/152182) while in subpopulation NFE AF= 0.000206 (14/68030). AF 95% confidence interval is 0.000124. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJB6	NM_058246.4 linkuse as main transcript	c.602G>A	p.Arg201Lys	missense_variant	7/10	ENST00000262177.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB6	ENST00000262177.9 linkuse as main transcript	c.602G>A	p.Arg201Lys	missense_variant	7/10	1	NM_058246.4		O75190-1

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251300

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461708

Hom.:

Cov.:

AF XY:

0.0000963

AC XY:

AN XY:

727156

show subpopulations

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:

0.000168

Gnomad4 NFE exome

AF:

0.0000953

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000261

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 24, 2023

The c.602G>A (p.R201K) alteration is located in exon 7 (coding exon 6) of the DNAJB6 gene. This alteration results from a G to A substitution at nucleotide position 602, causing the arginine (R) at amino acid position 201 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 201 of the DNAJB6 protein (p.Arg201Lys). This variant is present in population databases (rs373070679, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DNAJB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 286265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAJB6 protein function with a negative predictive value of 80%. 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Benign

0.91

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.60

T;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

N;N;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.84

N;N;N;.

REVEL

Benign

0.069

Sift

Benign

0.60

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0040

B;B;.;.

Vest4

0.31

MVP

0.53

MPC

0.36

ClinPred

0.070

GERP RS

4.2

Varity_R

0.19

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over