rs1645080178

Variant names:

• chr1-65309824-G-T
• rs1645080178
• NM_001256864.2:c.79G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001256864.2(DNAJC6):​c.79G>T​(p.Asp27Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000194 in 1,549,400 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• atypical juvenile parkinsonism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256864.2. 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
	DNAJC6	NM_001256864.2	MANE Select	c.79G>T	p.Asp27Tyr	missense	Exon 1 of 19	NP_001243793.1	O75061-2
	DNAJC6	NM_014787.4		c.22+44892G>T		intron	N/A	NP_055602.1	O75061-1
	DNAJC6	NM_001256865.2		c.-130-35787G>T		intron	N/A	NP_001243794.1	O75061-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC6	ENST00000371069.5	TSL:1 MANE Select	c.79G>T	p.Asp27Tyr	missense	Exon 1 of 19	ENSP00000360108.4	O75061-2
	DNAJC6	ENST00000395325.7	TSL:1	c.22+44892G>T		intron	N/A	ENSP00000378735.3	O75061-1
	DNAJC6	ENST00000263441.11	TSL:2	c.-130-35787G>T		intron	N/A	ENSP00000263441.7	O75061-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397226 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 689178

African (AFR) AF: 0.00 AC: 0 AN: 31322

American (AMR) AF: 0.00 AC: 0 AN: 35660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35618

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078470

Other (OTH) AF: 0.00 AC: 0 AN: 57948

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Juvenile onset Parkinson disease 19A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Pathogenic	0.89	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.25		Gain of sheet (P = 0.0061)
MVP		0.36
MPC		0.96
ClinPred		0.94	D
GERP RS		4.0
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
gMVP		0.47
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1645080178; hg19: chr1-65775507;