7-157358540-C-T

Variant names:

• chr7-157358540-C-T
• rs3802100
• NM_058246.4:c.-26-7C>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.-26-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,596,402 control chromosomes in the GnomAD database, including 262,231 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23231 hom., cov: 31)
  • Exomes 𝑓: 0.57 (239000 hom.)
• Consequence: DNAJB6 NM_058246.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002081
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.543
• Publications: 10 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 7-157358540-C-T is Benign according to our data. Variant chr7-157358540-C-T is described in ClinVar as Benign. ClinVar VariationId is 262304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJB6	NM_058246.4	c.-26-7C>T		splice_region_variant, intron_variant	Intron 1 of 9	ENST00000262177.9	NP_490647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJB6	ENST00000262177.9	c.-26-7C>T		splice_region_variant, intron_variant	Intron 1 of 9	1	NM_058246.4	ENSP00000262177.4

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83223 AN: 151798 Hom.: 23188 Cov.: 31

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.572

GnomAD2 exomes AF: 0.578 AC: 144571 AN: 250318 AF XY: 0.575

Gnomad AFR exome AF: 0.454

Gnomad AMR exome AF: 0.616

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.773

Gnomad FIN exome AF: 0.553

Gnomad NFE exome AF: 0.575

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.573 AC: 827895 AN: 1444486 Hom.: 239000 Cov.: 26 AF XY: 0.572 AC XY: 411791 AN XY: 719720

African (AFR) AF: 0.454 AC: 15020 AN: 33080

American (AMR) AF: 0.610 AC: 27178 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.519 AC: 13488 AN: 26000

East Asian (EAS) AF: 0.748 AC: 29618 AN: 39596

South Asian (SAS) AF: 0.533 AC: 45725 AN: 85806

European-Finnish (FIN) AF: 0.548 AC: 29248 AN: 53348

Middle Eastern (MID) AF: 0.545 AC: 2789 AN: 5122

European-Non Finnish (NFE) AF: 0.575 AC: 630955 AN: 1097284

Other (OTH) AF: 0.568 AC: 33874 AN: 59680

GnomAD4 genome AF: 0.548 AC: 83321 AN: 151916 Hom.: 23231 Cov.: 31 AF XY: 0.553 AC XY: 41038 AN XY: 74236

African (AFR) AF: 0.455 AC: 18833 AN: 41430

American (AMR) AF: 0.598 AC: 9136 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1731 AN: 3470

East Asian (EAS) AF: 0.755 AC: 3901 AN: 5166

South Asian (SAS) AF: 0.533 AC: 2563 AN: 4808

European-Finnish (FIN) AF: 0.554 AC: 5831 AN: 10526

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.580 AC: 39418 AN: 67936

Other (OTH) AF: 0.575 AC: 1215 AN: 2112

Alfa AF: 0.568 Hom.: 95272

Bravo AF: 0.548

Asia WGS AF: 0.612 AC: 2129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Limb-Girdle Muscular Dystrophy, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.6
DANN	Benign	0.71
PhyloP100		0.54
PromoterAI		-0.014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs3802100; hg19: chr7-157151234; COSMIC: COSV51096140; COSMIC: COSV51096140;