1-7962813-C-G

Variant names:

• chr1-7962813-C-G
• rs1309873819
• NM_007262.5:c.28C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_007262.5(PARK7):​c.28C>G​(p.Leu10Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,611,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PARK7 NM_007262.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a mutagenesis_site Abolishes detoxification activity on methylglyocal-adducted CoA. (size 0) in uniprot entity PARK7_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARK7	NM_007262.5	c.28C>G	p.Leu10Val	missense_variant	Exon 2 of 7	ENST00000338639.10	NP_009193.2
PARK7	NM_001123377.2	c.28C>G	p.Leu10Val	missense_variant	Exon 2 of 7		NP_001116849.1
PARK7	XM_005263424.4	c.28C>G	p.Leu10Val	missense_variant	Exon 2 of 7		XP_005263481.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARK7	ENST00000338639.10	c.28C>G	p.Leu10Val	missense_variant	Exon 2 of 7	1	NM_007262.5	ENSP00000340278.5

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150290 Hom.: 0 Cov.: 31

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461262 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726954

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150290 Hom.: 0 Cov.: 31 AF XY: 0.0000137 AC XY: 1 AN XY: 73178

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive early-onset Parkinson disease 7 Uncertain:1

Nov 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with PARK7-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 10 of the PARK7 protein (p.Leu10Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;T;T;T;T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	.;.;.;D;.;D
M_CAP	Uncertain	0.092	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.3	M;M;M;.;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	.;N;N;.;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.15	.;T;T;.;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T
Polyphen		0.57	P;P;P;.;P;P
Vest4		0.74, 0.74, 0.70
MutPred		0.54		Gain of catalytic residue at L10 (P = 0.0438);Gain of catalytic residue at L10 (P = 0.0438);Gain of catalytic residue at L10 (P = 0.0438);Gain of catalytic residue at L10 (P = 0.0438);Gain of catalytic residue at L10 (P = 0.0438);Gain of catalytic residue at L10 (P = 0.0438);
MVP		0.78
MPC		0.21
ClinPred		0.73	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.68
gMVP		0.68

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: rs1309873819; hg19: chr1-8022873;