rs387907047

Variant names:

• chr7-157367424-C-G
• rs387907047
• NM_058246.4:c.287C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-157367424-C-G
• chr7-157367424-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_058246.4(DNAJB6):​c.287C>G​(p.Pro96Arg) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P96L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.32

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 Pathogenic. Variant got 15 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-157367424-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 7-157367424-C-G is Pathogenic according to our data. Variant chr7-157367424-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 30905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-157367424-C-G is described in Lovd as [Pathogenic]. Variant chr7-157367424-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.287C>G	p.Pro96Arg	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	c.287C>G	p.Pro96Arg	missense_variant	Exon 5 of 10	1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Pathogenic:2

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces proline with arginine at codon 96 of the DNAJB6 protein (p.Pro96Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with distal myopathy (PMID: 22334415). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30905). Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 24920671, 26371419). This variant disrupts the p.Pro96 amino acid residue in DNAJB6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27671536, 28233300). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Apr 19, 2017

Eurofins Ntd Llc (ga)

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	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;D;.;T;.;T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.4	.;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;D;.;D;.;.;.
Vest4		0.92, 0.96, 0.85, 0.97
MutPred		0.42		Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);Gain of methylation at P96 (P = 0.0383);
MVP		0.89
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.85
gMVP		0.98

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: rs387907047; hg19: chr7-157160118;