7-157358620-C-T

Variant names:

• chr7-157358620-C-T
• rs150583876
• NM_058246.4:c.48C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_058246.4(DNAJB6):​c.48C>T​(p.Pro16Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P16P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (2 hom.)
• Consequence: DNAJB6 NM_058246.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.90
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.094).
• BP6: Variant 7-157358620-C-T is Benign according to our data. Variant chr7-157358620-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282322.
• BP7: Synonymous conserved (PhyloP=-1.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000473 (72/152244) while in subpopulation AFR AF = 0.00156 (65/41548). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 72 AD gene.

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.48C>T	p.Pro16Pro	synonymous	Exon 2 of 10	NP_490647.1
	DNAJB6	NM_005494.3		c.48C>T	p.Pro16Pro	synonymous	Exon 2 of 8	NP_005485.1
	DNAJB6	NM_001363676.1		c.48C>T	p.Pro16Pro	synonymous	Exon 2 of 7	NP_001350605.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJB6	ENST00000262177.9	TSL:1 MANE Select	c.48C>T	p.Pro16Pro	synonymous	Exon 2 of 10	ENSP00000262177.4
	DNAJB6	ENST00000429029.6	TSL:1	c.48C>T	p.Pro16Pro	synonymous	Exon 2 of 8	ENSP00000397556.2
	DNAJB6	ENST00000459889.5	TSL:1	n.48C>T		non_coding_transcript_exon	Exon 2 of 10	ENSP00000488263.1

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000143 AC: 36 AN: 251418 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000691 AC: 101 AN: 1460864 Hom.: 2 Cov.: 30 AF XY: 0.0000537 AC XY: 39 AN XY: 726844

African (AFR) AF: 0.00227 AC: 76 AN: 33454

American (AMR) AF: 0.000157 AC: 7 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111118

Other (OTH) AF: 0.000149 AC: 9 AN: 60354

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33 AN XY: 74430

African (AFR) AF: 0.00156 AC: 65 AN: 41548

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000574

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.2
DANN	Uncertain	0.98
PhyloP100		-1.9
PromoterAI		-0.038	Neutral

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: rs150583876; hg19: chr7-157151314;