2-232768776-T-C

Variant names:

• chr2-232768776-T-C
• rs746501620
• NM_002242.4:c.498A>G
• KCNJ13 p.Arg166Arg

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_001172416.1(KCNJ13):​c.262A>G​(p.Ser88Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,601,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNJ13 NM_001172416.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.35
• Publications: 0 publications found

Genes affected

KCNJ13 (HGNC:6259): (potassium inwardly rectifying channel subfamily J member 13) This gene encodes a member of the inwardly rectifying potassium channel family of proteins. Members of this family form ion channel pores that allow potassium ions to pass into a cell. The encoded protein belongs to a subfamily of low signal channel conductance proteins that have a low dependence on potassium concentration. Mutations in this gene are associated with snowflake vitreoretinal degeneration. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]

GIGYF2 (HGNC:11960): (GRB10 interacting GYF protein 2) This gene contains CAG trinucleotide repeats and encodes a protein containing several stretches of polyglutamine residues. The encoded protein may be involved in the regulation of tyrosine kinase receptor signaling. This gene is located in a chromosomal region that was genetically linked to Parkinson disease type 11, and mutations in this gene were thought to be causative for this disease. However, more recent studies in different populations have been unable to replicate this association. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2013]

GIGYF2 Gene-Disease associations (from GenCC):

• Parkinson disease 11, autosomal dominant, susceptibility to

  Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_001172416.1
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046067268).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172416.1. 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
	KCNJ13	NM_002242.4	MANE Select	c.498A>G	p.Arg166Arg	synonymous	Exon 3 of 3	NP_002233.2	O60928-1
	GIGYF2	NM_001103146.3	MANE Select	c.532+7340T>C		intron	N/A	NP_001096616.1	Q6Y7W6-1
	KCNJ13	NM_001172416.1		c.262A>G	p.Ser88Gly	missense	Exon 3 of 3	NP_001165887.1	O60928-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ13	ENST00000233826.4	TSL:1 MANE Select	c.498A>G	p.Arg166Arg	synonymous	Exon 3 of 3	ENSP00000233826.3	O60928-1
	KCNJ13	ENST00000410029.1	TSL:1	c.498A>G	p.Arg166Arg	synonymous	Exon 2 of 2	ENSP00000386251.1	O60928-1
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.532+7340T>C		intron	N/A	ENSP00000362664.5	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 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: 0.00

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: 0.00000276 AC: 4 AN: 1449104 Hom.: 0 Cov.: 32 AF XY: 0.00000278 AC XY: 2 AN XY: 718600

African (AFR) AF: 0.00 AC: 0 AN: 33016

American (AMR) AF: 0.00 AC: 0 AN: 43506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39390

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85484

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103118

Other (OTH) AF: 0.00 AC: 0 AN: 59768

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000312 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	9.3
DANN	Uncertain	0.99
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.046	T
MetaSVM	Uncertain	0.088	D
PhyloP100		1.4
PROVEAN	Benign	0.77	N
REVEL	Benign	0.21
Sift	Benign	0.46	T
Mutation Taster		=74/26	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs746501620;

hg19: chr2-233633486;