1-65389615-C-T

Variant names:

• chr1-65389615-C-T
• rs78141380
• NM_001256864.2:c.1456C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256864.2(DNAJC6):​c.1456C>T​(p.Leu486Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00204 in 1,614,060 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.69
• Publications: 5 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070246756).
• BP6: Variant 1-65389615-C-T is Benign according to our data. Variant chr1-65389615-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1637/152280) while in subpopulation AFR AF = 0.0381 (1581/41536). AF 95% confidence interval is 0.0365. There are 22 homozygotes in GnomAd4. There are 754 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC6	NM_001256864.2	MANE Select	c.1456C>T	p.Leu486Phe	missense	Exon 11 of 19	NP_001243793.1
	DNAJC6	NM_014787.4		c.1285C>T	p.Leu429Phe	missense	Exon 11 of 19	NP_055602.1
	DNAJC6	NM_001256865.2		c.1246C>T	p.Leu416Phe	missense	Exon 12 of 20	NP_001243794.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAJC6	ENST00000371069.5	TSL:1 MANE Select	c.1456C>T	p.Leu486Phe	missense	Exon 11 of 19	ENSP00000360108.4
	DNAJC6	ENST00000395325.7	TSL:1	c.1285C>T	p.Leu429Phe	missense	Exon 11 of 19	ENSP00000378735.3
	DNAJC6	ENST00000263441.11	TSL:2	c.1246C>T	p.Leu416Phe	missense	Exon 12 of 20	ENSP00000263441.7

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1635 AN: 152162 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00276 AC: 693 AN: 251382 AF XY: 0.00208

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00113 AC: 1651 AN: 1461780 Hom.: 28 Cov.: 31 AF XY: 0.000938 AC XY: 682 AN XY: 727190

African (AFR) AF: 0.0416 AC: 1391 AN: 33472

American (AMR) AF: 0.00139 AC: 62 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1111924

Other (OTH) AF: 0.00245 AC: 148 AN: 60392

GnomAD4 genome AF: 0.0107 AC: 1637 AN: 152280 Hom.: 22 Cov.: 32 AF XY: 0.0101 AC XY: 754 AN XY: 74470

African (AFR) AF: 0.0381 AC: 1581 AN: 41536

American (AMR) AF: 0.00248 AC: 38 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00379 Hom.: 38

Bravo AF: 0.0122

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00357 AC: 433

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Juvenile onset Parkinson disease 19A Benign:3

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Apr 28, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0070	T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.37
MVP		0.66
MPC		0.35
ClinPred		0.024	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.37
Mutation Taster		=92/8	polymorphism

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: rs78141380; hg19: chr1-65855298;