rs3738136

Variant names:

• chr1-20645618-G-A
• rs3738136
• NM_032409.3:c.1018G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032409.3(PINK1):​c.1018G>A​(p.Ala340Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0641 in 1,613,752 control chromosomes in the GnomAD database, including 5,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (462 hom., cov: 31)
  • Exomes 𝑓: 0.065 (5413 hom.)
• Consequence: PINK1 NM_032409.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.03
• Publications: 47 publications found

Genes affected

PINK1 (HGNC:14581): (PTEN induced kinase 1) This gene encodes a serine/threonine protein kinase that localizes to mitochondria. It is thought to protect cells from stress-induced mitochondrial dysfunction. Mutations in this gene cause one form of autosomal recessive early-onset Parkinson disease. [provided by RefSeq, Jul 2008]

PINK1-AS (HGNC:38872): (PINK1 antisense RNA)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056702495).
• BP6: Variant 1-20645618-G-A is Benign according to our data. Variant chr1-20645618-G-A is described in ClinVar as Benign. ClinVar VariationId is 295004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032409.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	NM_032409.3	MANE Select	c.1018G>A	p.Ala340Thr	missense	Exon 5 of 8	NP_115785.1	Q9BXM7-1
	PINK1-AS	NR_046507.1		n.3948C>T		non_coding_transcript_exon	Exon 2 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.1018G>A	p.Ala340Thr	missense	Exon 5 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.1018G>A	p.Ala340Thr	missense	Exon 5 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.1018G>A	p.Ala340Thr	missense	Exon 5 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.0548 AC: 8320 AN: 151828 Hom.: 461 Cov.: 31

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0627

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0479

GnomAD2 exomes AF: 0.0921 AC: 23161 AN: 251368 AF XY: 0.0971

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.0362

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.0930

Gnomad NFE exome AF: 0.0451

Gnomad OTH exome AF: 0.0701

GnomAD4 exome AF: 0.0651 AC: 95106 AN: 1461814 Hom.: 5413 Cov.: 38 AF XY: 0.0696 AC XY: 50621 AN XY: 727216

African (AFR) AF: 0.0130 AC: 434 AN: 33480

American (AMR) AF: 0.0947 AC: 4236 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 1079 AN: 26136

East Asian (EAS) AF: 0.258 AC: 10228 AN: 39694

South Asian (SAS) AF: 0.215 AC: 18563 AN: 86258

European-Finnish (FIN) AF: 0.0929 AC: 4962 AN: 53398

Middle Eastern (MID) AF: 0.0371 AC: 214 AN: 5766

European-Non Finnish (NFE) AF: 0.0460 AC: 51105 AN: 1111972

Other (OTH) AF: 0.0710 AC: 4285 AN: 60388

GnomAD4 genome AF: 0.0547 AC: 8316 AN: 151938 Hom.: 462 Cov.: 31 AF XY: 0.0600 AC XY: 4459 AN XY: 74268

African (AFR) AF: 0.0163 AC: 678 AN: 41472

American (AMR) AF: 0.0629 AC: 959 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.260 AC: 1333 AN: 5126

South Asian (SAS) AF: 0.229 AC: 1097 AN: 4800

European-Finnish (FIN) AF: 0.0869 AC: 916 AN: 10538

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0448 AC: 3047 AN: 67974

Other (OTH) AF: 0.0474 AC: 100 AN: 2108

Alfa AF: 0.0491 Hom.: 1330

Bravo AF: 0.0496

TwinsUK AF: 0.0440 AC: 163

ALSPAC AF: 0.0446 AC: 172

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.0473 AC: 407

ExAC AF: 0.0921 AC: 11176

Asia WGS AF: 0.203 AC: 703 AN: 3478

EpiCase AF: 0.0425

EpiControl AF: 0.0451

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive early-onset Parkinson disease 6 (3)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	PINK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.7
DANN	Benign	0.76
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.42	N
PhyloP100		1.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.054
MPC		0.17
ClinPred		0.0016	T
GERP RS		2.4
Varity_R		0.015
gMVP		0.34
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3738136; hg19: chr1-20972111; COSMIC: COSV58631402;