7-157366505-A-G

Variant names:

• chr7-157366505-A-G
• rs1057518860
• NM_058246.4:c.179A>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_058246.4(DNAJB6):​c.179A>G​(p.Lys60Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Interaction with HSP70 (size 144) in uniprot entity DNJB6_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_058246.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.179A>G	p.Lys60Arg	missense_variant	Exon 4 of 10	ENST00000262177.9	NP_490647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB6	ENST00000262177.9	c.179A>G	p.Lys60Arg	missense_variant	Exon 4 of 10	1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Muscle weakness;C0221629:Proximal muscle weakness Uncertain:1

Sep 19, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 60 of the DNAJB6 protein (p.Lys60Arg). This variant is not present in population databases (gnomAD no frequency). 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: 374048). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;.;T;.;T;T;.;T;T
Eigen	Benign	0.065
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	0.27	.;N;N;.;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.17	T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.13	T;T;T;T;D;T;T;T;T
Polyphen		0.28, 0.24, 0.18	.;B;B;.;B;.;.;.;.
Vest4		0.27, 0.25, 0.26
MutPred		0.43		Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);Loss of ubiquitination at K60 (P = 0.0098);
MVP		0.63
MPC		0.52
ClinPred		0.46	T
GERP RS		4.8
Varity_R		0.17
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518860; hg19: chr7-157159199;