1-65364630-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001256864.2(DNAJC6):c.194-5G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0029 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAJC6 NM_001256864.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002371
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0900

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-65364630-G-T is Benign according to our data. Variant chr1-65364630-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 474676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65364630-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC6	NM_001256864.2	c.194-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371069.5
DNAJC6	NM_001256865.2	c.-17-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DNAJC6	NM_014787.4	c.23-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC6	ENST00000371069.5	c.194-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001256864.2	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 314 AN: 99622 Hom.: 0 Cov.: 26 FAILED QC

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00489

Gnomad AMR AF: 0.00586

Gnomad ASJ AF: 0.00200

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.000982

Gnomad FIN AF: 0.00865

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00217

GnomAD3 exomes AF: 0.00359 AC: 342 AN: 95330 Hom.: 0 AF XY: 0.00349 AC XY: 181 AN XY: 51790

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.00622

Gnomad EAS exome AF: 0.0113

Gnomad SAS exome AF: 0.00491

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.00216

Gnomad OTH exome AF: 0.00457

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00289 AC: 3167 AN: 1094870 Hom.: 0 Cov.: 34 AF XY: 0.00339 AC XY: 1805 AN XY: 532844

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0196

Gnomad4 ASJ exome AF: 0.00625

Gnomad4 EAS exome AF: 0.00903

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.00465

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00346

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00315 AC: 314 AN: 99662 Hom.: 0 Cov.: 26 AF XY: 0.00374 AC XY: 178 AN XY: 47590

Gnomad4 AFR AF: 0.00112

Gnomad4 AMR AF: 0.00586

Gnomad4 ASJ AF: 0.00200

Gnomad4 EAS AF: 0.0131

Gnomad4 SAS AF: 0.000986

Gnomad4 FIN AF: 0.00865

Gnomad4 NFE AF: 0.00284

Gnomad4 OTH AF: 0.00216

Alfa AF: 0.0130 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile onset Parkinson disease 19A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2023	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.8
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs753576283; hg19: chr1-65830313;