rs45499398

Variant names:

• chr1-20648554-T-C
• rs45499398
• NM_032409.3:c.1173T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032409.3(PINK1):​c.1173T>C​(p.Asp391Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,614,130 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: PINK1 NM_032409.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.394
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-20648554-T-C is Benign according to our data. Variant chr1-20648554-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 534248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.394 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0109 (1655/152280) while in subpopulation AFR AF = 0.0372 (1544/41548). AF 95% confidence interval is 0.0356. There are 28 homozygotes in GnomAd4. There are 752 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AD,AR gene

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.1173T>C	p.Asp391Asp	synonymous	Exon 6 of 8	NP_115785.1	Q9BXM7-1
	PINK1-AS	NR_046507.1		n.3640A>G		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINK1	ENST00000321556.5	TSL:1 MANE Select	c.1173T>C	p.Asp391Asp	synonymous	Exon 6 of 8	ENSP00000364204.3	Q9BXM7-1
	PINK1	ENST00000878749.1		c.1173T>C	p.Asp391Asp	synonymous	Exon 6 of 8	ENSP00000548808.1
	PINK1	ENST00000878743.1		c.1173T>C	p.Asp391Asp	synonymous	Exon 6 of 8	ENSP00000548802.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1653 AN: 152162 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00302 AC: 758 AN: 251254 AF XY: 0.00219

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00106 AC: 1546 AN: 1461850 Hom.: 18 Cov.: 31 AF XY: 0.000897 AC XY: 652 AN XY: 727224

African (AFR) AF: 0.0349 AC: 1170 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000803 AC: 21 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111996

Other (OTH) AF: 0.00286 AC: 173 AN: 60394

GnomAD4 genome AF: 0.0109 AC: 1655 AN: 152280 Hom.: 28 Cov.: 33 AF XY: 0.0101 AC XY: 752 AN XY: 74468

African (AFR) AF: 0.0372 AC: 1544 AN: 41548

American (AMR) AF: 0.00516 AC: 79 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68010

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00843 Hom.: 29

Bravo AF: 0.0124

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Autosomal recessive early-onset Parkinson disease 6 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.0
DANN	Benign	0.62
PhyloP100		-0.39
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45499398; hg19: chr1-20975047;