rs149588872

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001256864.2(DNAJC6):c.745A>G(p.Ile249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,589,712 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 5 hom. )

Consequence

DNAJC6
NM_001256864.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.419

Publications

3 publications found

Variant links:

Genes affected

DNAJC6 (HGNC:15469): (DnaJ heat shock protein family (Hsp40) member C6) DNAJC6 belongs to the evolutionarily conserved DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity. DNAJ proteins may have up to 3 distinct domains: a conserved 70-amino acid J domain, usually at the N terminus, a glycine/phenylalanine (G/F)-rich region, and a cysteine-rich domain containing 4 motifs resembling a zinc finger domain (Ohtsuka and Hata, 2000 [PubMed 11147971]).[supplied by OMIM, Mar 2008]

DNAJC6 Gene-Disease associations (from GenCC):

juvenile onset Parkinson disease 19A
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
atypical juvenile parkinsonism
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
young-onset Parkinson disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DNAJC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009508282).

BP6

Variant 1-65384271-A-G is Benign according to our data. Variant chr1-65384271-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 541544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC6	NM_001256864.2 link	c.745A>G	p.Ile249Val	missense_variant	Exon 6 of 19	ENST00000371069.5	NP_001243793.1	O75061-2
DNAJC6	NM_014787.4 link	c.574A>G	p.Ile192Val	missense_variant	Exon 6 of 19		NP_055602.1	O75061-1
DNAJC6	NM_001256865.2 link	c.535A>G	p.Ile179Val	missense_variant	Exon 7 of 20		NP_001243794.1	O75061-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC6	ENST00000371069.5 link	c.745A>G	p.Ile249Val	missense_variant	Exon 6 of 19	1	NM_001256864.2	ENSP00000360108.4		O75061-2

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

503

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00948

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00118

AC:

272

AN:

229944

AF XY:

0.000922

show subpopulations

Gnomad AFR exome

AF:

0.00872

Gnomad AMR exome

AF:

0.000832

Gnomad ASJ exome

AF:

0.00998

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000931

GnomAD4 exome

AF:

0.000669

AC:

962

AN:

1437396

Hom.:

Cov.:

AF XY:

0.000616

AC XY:

440

AN XY:

714634

show subpopulations

African (AFR)

AF:

0.00894

AC:

287

AN:

32110

American (AMR)

AF:

0.00103

AC:

AN:

39998

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

280

AN:

25730

East Asian (EAS)

AF:

0.00

AC:

AN:

37640

South Asian (SAS)

AF:

0.0000366

AC:

AN:

81888

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53212

Middle Eastern (MID)

AF:

0.00192

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.000208

AC:

229

AN:

1101732

Other (OTH)

AF:

0.00185

AC:

110

AN:

59368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00330

AC:

502

AN:

152316

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

234

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00943

AC:

392

AN:

41574

American (AMR)

AF:

0.00262

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00244

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00840

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00132

AC:

160

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAJC6: BS2 -

Jun 22, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Juvenile onset Parkinson disease 19A

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DNAJC6-related disorder

Benign:1

Oct 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

5.8

(source)

DANN

Benign

0.27

DEOGEN2

Benign

0.074

.;.;T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.0095

T;T;T;T

MetaSVM

Uncertain

-0.015

MutationAssessor

Benign

1.4

.;.;L;.

PhyloP100

0.42

PrimateAI

Benign

0.33

PROVEAN

Benign

0.33

.;N;N;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;.;B;B

Vest4

0.11, 0.12, 0.12

MVP

0.29

MPC

0.22

ClinPred

0.0033

GERP RS

-3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.024

gMVP

0.27

Mutation Taster

=97/3

polymorphism

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over