chr1-65309899-C-G

Variant names:

• chr1-65309899-C-G
• rs547312338
• NM_001256864.2:c.154C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256864.2(DNAJC6):​c.154C>G​(p.Arg52Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,539,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R52R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07602489).

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.154C>G	p.Arg52Gly	missense	Exon 1 of 19	NP_001243793.1	O75061-2
	DNAJC6	NM_014787.4		c.22+44967C>G		intron	N/A	NP_055602.1	O75061-1
	DNAJC6	NM_001256865.2		c.-130-35712C>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.154C>G	p.Arg52Gly	missense	Exon 1 of 19	ENSP00000360108.4	O75061-2
	DNAJC6	ENST00000395325.7	TSL:1	c.22+44967C>G		intron	N/A	ENSP00000378735.3	O75061-1
	DNAJC6	ENST00000263441.11	TSL:2	c.-130-35712C>G		intron	N/A	ENSP00000263441.7	O75061-4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152094 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000221 AC: 3 AN: 136014 AF XY: 0.0000272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000420

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000414

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000187 AC: 26 AN: 1387748 Hom.: 0 Cov.: 34 AF XY: 0.0000190 AC XY: 13 AN XY: 684226

African (AFR) AF: 0.0000327 AC: 1 AN: 30540

American (AMR) AF: 0.0000285 AC: 1 AN: 35104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24526

East Asian (EAS) AF: 0.00 AC: 0 AN: 34816

South Asian (SAS) AF: 0.00 AC: 0 AN: 78402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5500

European-Non Finnish (NFE) AF: 0.0000205 AC: 22 AN: 1073572

Other (OTH) AF: 0.0000348 AC: 2 AN: 57526

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 30 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.00 AC: 0 AN: 41560

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

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	0.13
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Benign	0.74
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.70	T
PhyloP100		3.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.24
Sift	Benign	0.26	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.23		Loss of solvent accessibility (P = 0.0023)
MVP		0.13
MPC		0.35
ClinPred		0.97	D
GERP RS		4.0
PromoterAI		0.0093	Neutral
gMVP		0.27
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs547312338; hg19: chr1-65775582;