rs149588872

Positions:

• chr1-65384271-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001256864.2(DNAJC6):​c.745A>G​(p.Ile249Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,589,712 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (5 hom.)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.419

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009508282).
• BP6: Variant 1-65384271-A-G is Benign according to our data. Variant chr1-65384271-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 541544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-65384271-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAJC6	NM_001256864.2	c.745A>G	p.Ile249Val	missense_variant	6/19	ENST00000371069.5	NP_001243793.1
DNAJC6	NM_014787.4	c.574A>G	p.Ile192Val	missense_variant	6/19		NP_055602.1
DNAJC6	NM_001256865.2	c.535A>G	p.Ile179Val	missense_variant	7/20		NP_001243794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAJC6	ENST00000371069.5	c.745A>G	p.Ile249Val	missense_variant	6/19	1	NM_001256864.2	ENSP00000360108	P4

Frequencies

GnomAD3 genomes AF: 0.00330 AC: 503 AN: 152198 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00118 AC: 272 AN: 229944 Hom.: 1 AF XY: 0.000922 AC XY: 115 AN XY: 124764

Gnomad AFR exome AF: 0.00872

Gnomad AMR exome AF: 0.000832

Gnomad ASJ exome AF: 0.00998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.000931

GnomAD4 exome AF: 0.000669 AC: 962 AN: 1437396 Hom.: 5 Cov.: 30 AF XY: 0.000616 AC XY: 440 AN XY: 714634

Gnomad4 AFR exome AF: 0.00894

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000366

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000208

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00330 AC: 502 AN: 152316 Hom.: 4 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74472

Gnomad4 AFR AF: 0.00943

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00256 Hom.: 2

Bravo AF: 0.00393

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00132 AC: 160

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	DNAJC6: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Juvenile onset Parkinson disease 19A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

DNAJC6-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.8
DANN	Benign	0.27
DEOGEN2	Benign	0.074	.;.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0095	T;T;T;T
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Benign	1.4	.;.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.33	.;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	1.0	.;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;B
Vest4		0.11, 0.12, 0.12
MVP		0.29
MPC		0.22
ClinPred		0.0033	T
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.024
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs149588872; hg19: chr1-65849954;