Genetic Variant NM_058246.4:c.69T>C (chr7-157363164-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_058246.4(DNAJB6):c.69T>C(p.Tyr23Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,599,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DNAJB6
NM_058246.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0950

Publications

0 publications found

Variant links:

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

DNAJB6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 7-157363164-T-C is Benign according to our data. Variant chr7-157363164-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 704403.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000173 (25/1446794) while in subpopulation AMR AF = 0.000184 (8/43478). AF 95% confidence interval is 0.0000908. There are 0 homozygotes in GnomAdExome4. There are 11 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 25 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAJB6	NM_058246.4	MANE Select	c.69T>C	p.Tyr23Tyr	synonymous	Exon 3 of 10	NP_490647.1
DNAJB6	NM_005494.3		c.69T>C	p.Tyr23Tyr	synonymous	Exon 3 of 8	NP_005485.1
DNAJB6	NM_001363676.1		c.69T>C	p.Tyr23Tyr	synonymous	Exon 3 of 7	NP_001350605.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAJB6	ENST00000262177.9	TSL:1 MANE Select	c.69T>C	p.Tyr23Tyr	synonymous	Exon 3 of 10	ENSP00000262177.4
DNAJB6	ENST00000429029.6	TSL:1	c.69T>C	p.Tyr23Tyr	synonymous	Exon 3 of 8	ENSP00000397556.2
DNAJB6	ENST00000459889.5	TSL:1	n.69T>C		non_coding_transcript_exon	Exon 3 of 10	ENSP00000488263.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000543

AC:

AN:

239498

AF XY:

0.0000233

show subpopulations

Gnomad AFR exome

AF:

0.0000674

Gnomad AMR exome

AF:

0.000270

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1446794

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

719160

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33270

American (AMR)

AF:

0.000184

AC:

AN:

43478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25830

East Asian (EAS)

AF:

0.00

AC:

AN:

39620

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000127

AC:

AN:

1102052

Other (OTH)

AF:

0.00

AC:

AN:

59966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41454

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000868

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.16

(source)

DANN

Benign

0.21

PhyloP100

-0.095

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over