NM_001256864.2:c.175A>G

Variant names:

• chr1-65309920-A-G
• rs1296532855
• NM_001256864.2:c.175A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001256864.2(DNAJC6):​c.175A>G​(p.Ser59Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000543 in 1,527,682 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000057 (1 hom.)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.37
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23849285).

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.175A>G	p.Ser59Gly	missense	Exon 1 of 19	NP_001243793.1	O75061-2
	DNAJC6	NM_014787.4		c.22+44988A>G		intron	N/A	NP_055602.1	O75061-1
	DNAJC6	NM_001256865.2		c.-130-35691A>G		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.175A>G	p.Ser59Gly	missense	Exon 1 of 19	ENSP00000360108.4	O75061-2
	DNAJC6	ENST00000395325.7	TSL:1	c.22+44988A>G		intron	N/A	ENSP00000378735.3	O75061-1
	DNAJC6	ENST00000263441.11	TSL:2	c.-130-35691A>G		intron	N/A	ENSP00000263441.7	O75061-4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152144 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: 0.000777

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 120900 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000574 AC: 79 AN: 1375420 Hom.: 1 Cov.: 34 AF XY: 0.0000591 AC XY: 40 AN XY: 677248

African (AFR) AF: 0.00 AC: 0 AN: 30016

American (AMR) AF: 0.00 AC: 0 AN: 34170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23618

East Asian (EAS) AF: 0.00228 AC: 78 AN: 34212

South Asian (SAS) AF: 0.00 AC: 0 AN: 76490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067584

Other (OTH) AF: 0.0000176 AC: 1 AN: 56958

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152262 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.000779 AC: 4 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	23
DANN	Benign	0.93
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.26	T
PhyloP100		7.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.32
Sift	Benign	0.55	T
Sift4G	Benign	0.59	T
Polyphen		0.043	B
Vest4		0.22
MutPred		0.17		Loss of phosphorylation at S59 (P = 0.0018)
MVP		0.49
MPC		0.27
ClinPred		0.91	D
GERP RS		4.0
PromoterAI		0.14	Neutral
gMVP		0.18
Mutation Taster		=75/25	polymorphism

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: rs1296532855; hg19: chr1-65775603;