rs398122404

Positions:

• chr1-65385710-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001256864.2(DNAJC6):​c.801-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJC6 NM_001256864.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 8.95

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.066598006 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of 32, new splice context is: tatgtgtgacctactggcAGaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-65385710-A-G is Pathogenic according to our data. Variant chr1-65385710-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 88854.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-65385710-A-G is described in Lovd as [Pathogenic]. Variant chr1-65385710-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC6	NM_001256864.2	c.801-2A>G		splice_acceptor_variant, intron_variant		ENST00000371069.5	NP_001243793.1
DNAJC6	NM_014787.4	c.630-2A>G		splice_acceptor_variant, intron_variant			NP_055602.1
DNAJC6	NM_001256865.2	c.591-2A>G		splice_acceptor_variant, intron_variant			NP_001243794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC6	ENST00000371069.5	c.801-2A>G		splice_acceptor_variant, intron_variant		1	NM_001256864.2	ENSP00000360108.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1431726 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 708176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Juvenile onset Parkinson disease 19A Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
not provided, no classification provided	literature only	GeneReviews	-	Juvenile-onset parkinsonism -

Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

Section for Clinical Neurogenetics, University of Tübingen

Aug 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: -21
DS_AL_spliceai		0.99		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398122404; hg19: chr1-65851393;