7-157367416-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS1_Very_StrongPM1PM2PP3PP5_Very_Strong

The NM_058246.4(DNAJB6):c.279C>G(p.Phe93Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F93F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

DNAJB6
NM_058246.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.03

Publications

40 publications found

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 Gene-Disease associations (from GenCC):

muscular dystrophy, limb-girdle, autosomal dominant
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

DNAJB6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 21 ACMG points.

PS1

Transcript NM_058246.4 (DNAJB6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_058246.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.745

PP5

Variant 7-157367416-C-G is Pathogenic according to our data. Variant chr7-157367416-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB6	NM_058246.4 link	c.279C>G	p.Phe93Leu	missense_variant	Exon 5 of 10	ENST00000262177.9	NP_490647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB6	ENST00000262177.9 link	c.279C>G	p.Phe93Leu	missense_variant	Exon 5 of 10	1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Jul 09, 2021

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. In vitro and in vivo experiments showed that this variant has a dominant toxic effect on the wild-type protein (PMID: 22366786). -

May 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM1, PM2, PS3, PS4 -

Jun 15, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The pathogenic F93L variant in the DNAJB6 gene has been reported multiple times in association with LGMD1D (Sarparanta et al., 2012; Sato et al., 2013; Sandell et al., 2016). Functional studies indicate that F93L increases the half-life of DNAJB6, which results in the toxic aggregation of DNAJB6 protein and its binding partners (Sarparanta et al., 2012). The F93L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although F93L is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. Additionally, missense variants in the same residue (F93I) and in nearby residues (F89I; F91I; P96R) have been reported in the Human Gene Mutation Database in association with myopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret F93L as a pathogenic variant, and its presence is consistent with a diagnosis of LGMD1D. -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAJB6: PS1, PM2, PM5, PP3, PS3:Supporting -

Sep 15, 2016

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:4

Sep 10, 2020

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 26, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 93 of the DNAJB6 protein (p.Phe93Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy (PMID: 22334415, 26205529, 26847086, 28794355). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31529). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt DNAJB6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 26847086). For these reasons, this variant has been classified as Pathogenic. -

Oct 11, 2022

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;D;.;T;.;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

T;T;T;T;T;T;T;T

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.74

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.2

.;M;M;.;.;.;.;.

PhyloP100

7.0

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;D;D;.

REVEL

Uncertain

0.60

Sift

Benign

0.039

D;D;D;D;D;T;T;.

Sift4G

Uncertain

0.059

T;T;T;D;T;T;T;T

Polyphen

1.0, 0.97, 0.20

.;D;D;.;B;.;.;.

Vest4

0.93, 0.94, 0.80, 0.96

MutPred

0.29

Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);Loss of phosphorylation at T92 (P = 0.2306);

MVP

0.87

MPC

1.1

ClinPred

0.98

GERP RS

4.6

Varity_R

0.60

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over