2-232768405-G-C

Variant names:

• chr2-232768405-G-C
• rs17853727
• NM_002242.4:c.869C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002242.4(KCNJ13):​c.869C>G​(p.Pro290Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P290L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ13 NM_002242.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3604054).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002242.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ13	NM_002242.4	MANE Select	c.869C>G	p.Pro290Arg	missense	Exon 3 of 3	NP_002233.2
	GIGYF2	NM_001103146.3	MANE Select	c.532+6969G>C		intron	N/A	NP_001096616.1
	KCNJ13	NM_001172417.1		c.629C>G	p.Pro210Arg	missense	Exon 3 of 3	NP_001165888.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ13	ENST00000233826.4	TSL:1 MANE Select	c.869C>G	p.Pro290Arg	missense	Exon 3 of 3	ENSP00000233826.3
	KCNJ13	ENST00000410029.1	TSL:1	c.869C>G	p.Pro290Arg	missense	Exon 2 of 2	ENSP00000386251.1
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.532+6969G>C		intron	N/A	ENSP00000362664.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111958

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.37	T
PhyloP100		5.0
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
MutPred		0.19		Gain of solvent accessibility (P = 0.0097)
MVP		0.60
ClinPred		0.93	D
GERP RS		5.9
PromoterAI		0.012	Neutral
Varity_R		0.76
Mutation Taster		=82/18	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

Other links and lift over

dbSNP: rs17853727; hg19: chr2-233633115;