7-157358540-C-T

Position:

• chr7-157358540-C-T

Variant summary

Our verdict is Benign. Variant got -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, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002081
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.543

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 Benign. Variant got -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 id 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/exons	MANE	UniProt
DNAJB6	NM_058246.4	c.-26-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262177.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJB6	ENST00000262177.9	c.-26-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_058246.4

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

GnomAD3 exomes AF: 0.578 AC: 144571 AN: 250318 Hom.: 42310 AF XY: 0.575 AC XY: 77820 AN XY: 135326

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 SAS exome AF: 0.528

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

Gnomad4 AFR exome AF: 0.454

Gnomad4 AMR exome AF: 0.610

Gnomad4 ASJ exome AF: 0.519

Gnomad4 EAS exome AF: 0.748

Gnomad4 SAS exome AF: 0.533

Gnomad4 FIN exome AF: 0.548

Gnomad4 NFE exome AF: 0.575

Gnomad4 OTH exome AF: 0.568

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

Gnomad4 AFR AF: 0.455

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.755

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.554

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.575

Alfa AF: 0.572 Hom.: 43419

Bravo AF: 0.548

Asia WGS AF: 0.612 AC: 2129 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.6
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs3802100; hg19: chr7-157151234; COSMIC: COSV51096140; COSMIC: COSV51096140;