1-65309899-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001256864.2(DNAJC6):​c.154C>T​(p.Arg52*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R52R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: DNAJC6 NM_001256864.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.154C>T	p.Arg52*	stop_gained	Exon 1 of 19	NP_001243793.1	O75061-2
	DNAJC6	NM_014787.4		c.22+44967C>T		intron	N/A	NP_055602.1	O75061-1
	DNAJC6	NM_001256865.2		c.-130-35712C>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.154C>T	p.Arg52*	stop_gained	Exon 1 of 19	ENSP00000360108.4	O75061-2
	DNAJC6	ENST00000395325.7	TSL:1	c.22+44967C>T		intron	N/A	ENSP00000378735.3	O75061-1
	DNAJC6	ENST00000263441.11	TSL:2	c.-130-35712C>T		intron	N/A	ENSP00000263441.7	O75061-4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387748 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 684226

African (AFR) AF: 0.00 AC: 0 AN: 30540

American (AMR) AF: 0.00 AC: 0 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: 9.31e-7 AC: 1 AN: 1073572

Other (OTH) AF: 0.00 AC: 0 AN: 57526

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.076	N
PhyloP100		3.4
Vest4		0.12
GERP RS		4.0
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=25/175	disease causing (fs/PTC)

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: rs547312338; hg19: chr1-65775582;