NM_007262.5:c.192G>C

Variant names:

• chr1-7965425-G-C
• rs74315353
• NM_007262.5:c.192G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_007262.5(PARK7):​c.192G>C​(p.Glu64Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PARK7 NM_007262.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.13

Genes affected

PARK7 (HGNC:16369): (Parkinsonism associated deglycase) The product of this gene belongs to the peptidase C56 family of proteins. It acts as a positive regulator of androgen receptor-dependent transcription. It may also function as a redox-sensitive chaperone, as a sensor for oxidative stress, and it apparently protects neurons against oxidative stress and cell death. Defects in this gene are the cause of autosomal recessive early-onset Parkinson disease 7. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-7965425-G-C is Pathogenic according to our data. Variant chr1-7965425-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7067.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-7965425-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARK7	NM_007262.5	c.192G>C	p.Glu64Asp	missense_variant, splice_region_variant	Exon 3 of 7	ENST00000338639.10	NP_009193.2
PARK7	NM_001123377.2	c.192G>C	p.Glu64Asp	missense_variant, splice_region_variant	Exon 3 of 7		NP_001116849.1
PARK7	XM_005263424.4	c.192G>C	p.Glu64Asp	missense_variant, splice_region_variant	Exon 3 of 7		XP_005263481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10	c.192G>C	p.Glu64Asp	missense_variant, splice_region_variant	Exon 3 of 7	1	NM_007262.5	ENSP00000340278.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 7 Pathogenic:1

Oct 01, 2004

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;T;T;T;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.43	.;.;.;T;.;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.35	N;N;N;.;N;N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.75	.;N;N;.;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.61	.;T;T;.;T;T;.
Sift4G	Benign	0.53	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;B;B;.
Vest4		0.37, 0.37, 0.31
MutPred		0.80		Loss of ubiquitination at K63 (P = 0.065);Loss of ubiquitination at K63 (P = 0.065);Loss of ubiquitination at K63 (P = 0.065);Loss of ubiquitination at K63 (P = 0.065);Loss of ubiquitination at K63 (P = 0.065);Loss of ubiquitination at K63 (P = 0.065);.;
MVP		0.97
MPC		0.11
ClinPred		0.59	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74315353; hg19: chr1-8025485;