rs28377945

Variant names:

• chr7-157366482-A-G
• rs28377945
• NM_058246.4:c.176-20A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-157366482-A-G
• chr7-157366482-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_058246.4(DNAJB6):​c.176-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0401 in 1,612,064 control chromosomes in the GnomAD database, including 1,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (222 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1273 hom.)
• Consequence: DNAJB6 NM_058246.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.66
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-157366482-A-G is Benign according to our data. Variant chr7-157366482-A-G is described in ClinVar as Benign. ClinVar VariationId is 262305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	NM_058246.4	MANE Select	c.176-20A>G		intron	N/A	NP_490647.1
	DNAJB6	NM_005494.3		c.176-20A>G		intron	N/A	NP_005485.1
	DNAJB6	NM_001363676.1		c.176-20A>G		intron	N/A	NP_001350605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	ENST00000262177.9	TSL:1 MANE Select	c.176-20A>G		intron	N/A	ENSP00000262177.4
	DNAJB6	ENST00000429029.6	TSL:1	c.176-20A>G		intron	N/A	ENSP00000397556.2
	DNAJB6	ENST00000459889.5	TSL:1	n.176-20A>G		intron	N/A	ENSP00000488263.1

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7522 AN: 152152 Hom.: 220 Cov.: 33

Gnomad AFR AF: 0.0802

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0493

GnomAD2 exomes AF: 0.0365 AC: 9154 AN: 251076 AF XY: 0.0361

Gnomad AFR exome AF: 0.0814

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0153

Gnomad EAS exome AF: 0.0145

Gnomad FIN exome AF: 0.0425

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0395

GnomAD4 exome AF: 0.0391 AC: 57150 AN: 1459794 Hom.: 1273 Cov.: 30 AF XY: 0.0387 AC XY: 28098 AN XY: 726308

African (AFR) AF: 0.0786 AC: 2626 AN: 33412

American (AMR) AF: 0.0219 AC: 979 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 368 AN: 26126

East Asian (EAS) AF: 0.0112 AC: 444 AN: 39660

South Asian (SAS) AF: 0.0301 AC: 2591 AN: 86126

European-Finnish (FIN) AF: 0.0430 AC: 2294 AN: 53324

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5766

European-Non Finnish (NFE) AF: 0.0409 AC: 45430 AN: 1110384

Other (OTH) AF: 0.0377 AC: 2275 AN: 60332

GnomAD4 genome AF: 0.0495 AC: 7532 AN: 152270 Hom.: 222 Cov.: 33 AF XY: 0.0483 AC XY: 3598 AN XY: 74442

African (AFR) AF: 0.0802 AC: 3334 AN: 41560

American (AMR) AF: 0.0320 AC: 489 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5180

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4822

European-Finnish (FIN) AF: 0.0393 AC: 417 AN: 10602

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0418 AC: 2843 AN: 68018

Other (OTH) AF: 0.0488 AC: 103 AN: 2112

Alfa AF: 0.0426 Hom.: 56

Bravo AF: 0.0493

Asia WGS AF: 0.0340 AC: 119 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.39
PhyloP100		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs28377945; hg19: chr7-157159176; COSMIC: COSV51100899; COSMIC: COSV51100899;