chr1-65309864-G-T

Variant names:

• chr1-65309864-G-T
• rs754115488
• NM_001256864.2:c.119G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256864.2(DNAJC6):​c.119G>T​(p.Arg40Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000355 in 1,548,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: DNAJC6 NM_001256864.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26136437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAJC6	NM_001256864.2	c.119G>T	p.Arg40Ile	missense_variant	Exon 1 of 19	ENST00000371069.5	NP_001243793.1
DNAJC6	NM_014787.4	c.22+44932G>T		intron_variant	Intron 1 of 18		NP_055602.1
DNAJC6	NM_001256865.2	c.-130-35747G>T		intron_variant	Intron 1 of 19		NP_001243794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAJC6	ENST00000371069.5	c.119G>T	p.Arg40Ile	missense_variant	Exon 1 of 19	1	NM_001256864.2	ENSP00000360108.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152100 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000136 AC: 2 AN: 146530 Hom.: 0 AF XY: 0.0000253 AC XY: 2 AN XY: 79050

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000358 AC: 50 AN: 1395924 Hom.: 0 Cov.: 34 AF XY: 0.0000392 AC XY: 27 AN XY: 688522

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: 0.0000464

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152100 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000580 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000534 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Juvenile onset Parkinson disease 19A Uncertain:1

Nov 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DNAJC6-related conditions. This variant is present in population databases (rs754115488, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 40 of the DNAJC6 protein (p.Arg40Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.95
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.53	T
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Benign	0.20	T
Sift4G	Benign	0.10	T
Polyphen		0.22	B
Vest4		0.34
MutPred		0.37		Gain of sheet (P = 0.0043);
MVP		0.29
MPC		0.54
ClinPred		0.75	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
gMVP		0.17

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: rs754115488; hg19: chr1-65775547;