chr1-65395019-G-A

Variant names:

• chr1-65395019-G-A
• rs185245369
• NM_001256864.2:c.2025G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001256864.2(DNAJC6):​c.2025G>A​(p.Ser675Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000907 in 1,609,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. S675S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: DNAJC6 NM_001256864.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.235
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 1-65395019-G-A is Benign according to our data. Variant chr1-65395019-G-A is described in ClinVar as Benign. ClinVar VariationId is 2051812.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.235 with no splicing effect.

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.2025G>A	p.Ser675Ser	synonymous	Exon 13 of 19	NP_001243793.1
	DNAJC6	NM_014787.4		c.1854G>A	p.Ser618Ser	synonymous	Exon 13 of 19	NP_055602.1
	DNAJC6	NM_001256865.2		c.1815G>A	p.Ser605Ser	synonymous	Exon 14 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.2025G>A	p.Ser675Ser	synonymous	Exon 13 of 19	ENSP00000360108.4
	DNAJC6	ENST00000395325.7	TSL:1	c.1854G>A	p.Ser618Ser	synonymous	Exon 13 of 19	ENSP00000378735.3
	DNAJC6	ENST00000263441.11	TSL:2	c.1815G>A	p.Ser605Ser	synonymous	Exon 14 of 20	ENSP00000263441.7

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000179 AC: 44 AN: 246414 AF XY: 0.000210

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.000226

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.0000864 AC: 126 AN: 1457784 Hom.: 0 Cov.: 32 AF XY: 0.0000883 AC XY: 64 AN XY: 725056

African (AFR) AF: 0.00 AC: 0 AN: 33110

American (AMR) AF: 0.0000455 AC: 2 AN: 44004

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 78 AN: 26062

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39280

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1110712

Other (OTH) AF: 0.000199 AC: 12 AN: 60284

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74376

African (AFR) AF: 0.0000241 AC: 1 AN: 41518

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3466

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DNAJC6-related disorder (1)
-	-	1	Juvenile onset Parkinson disease 19A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.5
DANN	Benign	0.33
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs185245369; hg19: chr1-65860702; COSMIC: COSV54773984; COSMIC: COSV54773984;