rs879255630

Positions:

• chr1-65411394-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001256864.2(DNAJC6):​c.2779A>G​(p.Arg927Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• PP5: Variant 1-65411394-A-G is Pathogenic according to our data. Variant chr1-65411394-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 253094.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC6	NM_001256864.2	c.2779A>G	p.Arg927Gly	missense_variant	18/19	ENST00000371069.5	NP_001243793.1
DNAJC6	NM_014787.4	c.2608A>G	p.Arg870Gly	missense_variant	18/19		NP_055602.1
DNAJC6	NM_001256865.2	c.2569A>G	p.Arg857Gly	missense_variant	19/20		NP_001243794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC6	ENST00000371069.5	c.2779A>G	p.Arg927Gly	missense_variant	18/19	1	NM_001256864.2	ENSP00000360108	P4
DNAJC6	ENST00000395325.7	c.2608A>G	p.Arg870Gly	missense_variant	18/19	1		ENSP00000378735	A1
DNAJC6	ENST00000263441.11	c.2569A>G	p.Arg857Gly	missense_variant	19/20	2		ENSP00000263441	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Parkinson disease 19B, early-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 09, 2016

- -

Juvenile onset Parkinson disease 19A Other:1

not provided, no classification provided

literature only

GeneReviews

-

Early-onset parkinsonism -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Pathogenic	4.7	.;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.4	D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92
MutPred		0.57		.;Loss of MoRF binding (P = 0.011);.;
MVP		0.70
MPC		1.1
ClinPred		1.0	D
GERP RS		-0.67
Varity_R		0.77
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs879255630; hg19: chr1-65877077;