NM_002242.4:c.484C>T

Variant names:

• chr2-232768790-G-A
• rs121918542
• NM_002242.4:c.484C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM2 PP3 PP5_Very_Strong BP4

The NM_002242.4(KCNJ13):​c.484C>T​(p.Arg162Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,450,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R162Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNJ13 NM_002242.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.04
• Publications: 23 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: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PROVEAN was below the threshold]
• PP5: Variant 2-232768790-G-A is Pathogenic according to our data. Variant chr2-232768790-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3361854). . Strength limited to SUPPORTING due to the PP5.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ13	NM_002242.4	MANE Select	c.484C>T	p.Arg162Trp	missense	Exon 3 of 3	NP_002233.2	O60928-1
	GIGYF2	NM_001103146.3	MANE Select	c.532+7354G>A		intron	N/A	NP_001096616.1	Q6Y7W6-1
	KCNJ13	NM_001172417.1		c.244C>T	p.Arg82Trp	missense	Exon 3 of 3	NP_001165888.1	O60928

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNJ13	ENST00000233826.4	TSL:1 MANE Select	c.484C>T	p.Arg162Trp	missense	Exon 3 of 3	ENSP00000233826.3	O60928-1
	KCNJ13	ENST00000410029.1	TSL:1	c.484C>T	p.Arg162Trp	missense	Exon 2 of 2	ENSP00000386251.1	O60928-1
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.532+7354G>A		intron	N/A	ENSP00000362664.5	Q6Y7W6-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247900 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450060 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719102

African (AFR) AF: 0.00 AC: 0 AN: 33136

American (AMR) AF: 0.00 AC: 0 AN: 43862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39380

South Asian (SAS) AF: 0.00 AC: 0 AN: 85502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103452

Other (OTH) AF: 0.00 AC: 0 AN: 59848

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Snowflake vitreoretinal degeneration (3)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.34	T
MetaSVM	Pathogenic	0.95	D
PhyloP100		5.0
PROVEAN	Benign	0.23	N
REVEL	Uncertain	0.41
Sift	Benign	0.053	T
Vest4		0.45
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0071)
MVP		0.64
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.92
Mutation Taster		=15/85	disease causing (ClinVar)

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: rs121918542; hg19: chr2-233633500; COSMIC: COSV52085600; COSMIC: COSV52085600;