rs2296481

chr1-65379393-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256864.2(DNAJC6):c.544-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,612,582 control chromosomes in the GnomAD database, including 32,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (8482 hom., cov: 32)
  • Exomes 𝑓: 0.12 (24066 hom.)
• Consequence: DNAJC6 NM_001256864.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001528
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.341

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 1-65379393-C-T is Benign according to our data. Variant chr1-65379393-C-T is described in ClinVar as [Benign]. Clinvar id is 1170298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65379393-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAJC6	NM_001256864.2	c.544-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371069.5
DNAJC6	NM_001256865.2	c.334-9C>T		splice_polypyrimidine_tract_variant, intron_variant
DNAJC6	NM_014787.4	c.373-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAJC6	ENST00000371069.5	c.544-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001256864.2	P4

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38236 AN: 151866 Hom.: 8461 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.212 AC: 53031 AN: 250576 Hom.: 9833 AF XY: 0.202 AC XY: 27311 AN XY: 135442

Gnomad AFR exome AF: 0.568

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.166

Gnomad EAS exome AF: 0.615

Gnomad SAS exome AF: 0.305

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.0658

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.118 AC: 171806 AN: 1460598 Hom.: 24066 Cov.: 31 AF XY: 0.121 AC XY: 88212 AN XY: 726606

Gnomad4 AFR exome AF: 0.574

Gnomad4 AMR exome AF: 0.272

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.304

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.252 AC: 38314 AN: 151984 Hom.: 8482 Cov.: 32 AF XY: 0.259 AC XY: 19216 AN XY: 74294

Gnomad4 AFR AF: 0.560

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.0646

Gnomad4 OTH AF: 0.219

Alfa AF: 0.151 Hom.: 1878

Bravo AF: 0.271

Asia WGS AF: 0.477 AC: 1660 AN: 3478

EpiCase AF: 0.0734

EpiControl AF: 0.0762

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Juvenile onset Parkinson disease 19A Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	16
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.22
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: rs2296481; hg19: chr1-65845076;