rs759982570

Variant names:

• chr7-157367410-C-G
• rs759982570
• NM_058246.4:c.273C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-157367410-C-G
• chr7-157367410-C-T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP5_Very_Strong

The NM_058246.4(DNAJB6):​c.273C>G​(p.Phe91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F91V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJB6 NM_058246.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.53
• 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 22 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr7-157367408-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 498056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 7-157367410-C-G is Pathogenic according to our data. Variant chr7-157367410-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 225176.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.273C>G	p.Phe91Leu	missense	Exon 5 of 10	NP_490647.1	O75190-1
	DNAJB6	NM_005494.3		c.273C>G	p.Phe91Leu	missense	Exon 5 of 8	NP_005485.1	O75190-2
	DNAJB6	NM_001363676.1		c.273C>G	p.Phe91Leu	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.273C>G	p.Phe91Leu	missense	Exon 5 of 10	ENSP00000262177.4	O75190-1
	DNAJB6	ENST00000429029.6	TSL:1	c.273C>G	p.Phe91Leu	missense	Exon 5 of 8	ENSP00000397556.2	O75190-2
	DNAJB6	ENST00000459889.5	TSL:1	n.273C>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
3	-	-	Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (3)
1	-	-	Abnormality of the musculature (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.0053
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	-0.095	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.5
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.27		Gain of catalytic residue at F91 (P = 0.1463)
MVP		0.95
MPC		1.0
ClinPred		0.97	D
GERP RS		0.53
Varity_R		0.43
gMVP		0.95
Mutation Taster		=2/98	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: rs759982570; hg19: chr7-157160104;