2-232766324-A-G

Variant names:

• chr2-232766324-A-G
• rs144253492
• NM_002242.4:c.*1867T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_002242.4(KCNJ13):​c.*1867T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 205,964 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KCNJ13 NM_002242.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000241409 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000985 (15/152346) while in subpopulation EAS AF = 0.0027 (14/5190). AF 95% confidence interval is 0.00163. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.*1867T>C		3_prime_UTR	Exon 3 of 3	NP_002233.2	O60928-1
	GIGYF2	NM_001103146.3	MANE Select	c.532+4888A>G		intron	N/A	NP_001096616.1	Q6Y7W6-1
	KCNJ13	NM_001172417.1		c.*1867T>C		3_prime_UTR	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.*1867T>C		3_prime_UTR	Exon 3 of 3	ENSP00000233826.3	O60928-1
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.532+4888A>G		intron	N/A	ENSP00000362664.5	Q6Y7W6-1
	GIGYF2	ENST00000409451.7	TSL:1	c.532+4888A>G		intron	N/A	ENSP00000387170.3	Q6Y7W6-3

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152228 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: 0.00269

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000224 AC: 12 AN: 53618 Hom.: 0 AF XY: 0.000211 AC XY: 6 AN XY: 28462

African (AFR) AF: 0.00 AC: 0 AN: 1026

American (AMR) AF: 0.00 AC: 0 AN: 3084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1140

East Asian (EAS) AF: 0.00503 AC: 12 AN: 2388

South Asian (SAS) AF: 0.00 AC: 0 AN: 8946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 186

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 31632

Other (OTH) AF: 0.00 AC: 0 AN: 2666

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leber congenital amaurosis 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.17
DANN	Benign	0.42
PhyloP100		-1.1

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: rs144253492; hg19: chr2-233631034;