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. The variant received 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
• Publications: 19 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 10 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-157367424-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2136635.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 VariationId is 30905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	NM_058246.4	MANE Select	c.287C>G	p.Pro96Arg	missense	Exon 5 of 10	NP_490647.1	O75190-1
	DNAJB6	NM_005494.3		c.287C>G	p.Pro96Arg	missense	Exon 5 of 8	NP_005485.1	O75190-2
	DNAJB6	NM_001363676.1		c.287C>G	p.Pro96Arg	missense	Exon 5 of 7	NP_001350605.1	E9PH18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	ENST00000262177.9	TSL:1 MANE Select	c.287C>G	p.Pro96Arg	missense	Exon 5 of 10	ENSP00000262177.4	O75190-1
	DNAJB6	ENST00000429029.6	TSL:1	c.287C>G	p.Pro96Arg	missense	Exon 5 of 8	ENSP00000397556.2	O75190-2
	DNAJB6	ENST00000459889.5	TSL:1	n.287C>G		non_coding_transcript_exon	Exon 5 of 10	ENSP00000488263.1	A0A0J9YX62

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.42		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907047; hg19: chr7-157160118;