chr2-232770905-G-A

Position:

• chr2-232770905-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_002242.4(KCNJ13):​c.458C>T​(p.Thr153Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ13 NM_002242.4 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-232770905-G-A is Pathogenic according to our data. Variant chr2-232770905-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216947.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-232770905-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-232770905-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ13	NM_002242.4	c.458C>T	p.Thr153Ile	missense_variant, splice_region_variant	2/3	ENST00000233826.4	NP_002233.2
GIGYF2	NM_001103146.3	c.532+9469G>A		intron_variant		ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ13	ENST00000233826.4	c.458C>T	p.Thr153Ile	missense_variant, splice_region_variant	2/3	1	NM_002242.4	ENSP00000233826	P1
GIGYF2	ENST00000373563.9	c.532+9469G>A		intron_variant		1	NM_001103146.3	ENSP00000362664	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis Pathogenic:1

Pathogenic, no assertion criteria provided

research

Rui Chen Lab, Baylor College of Medicine

May 09, 2017

- -

Leber congenital amaurosis 16 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Nov 20, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.90	L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.013	D;D;T
Sift4G	Benign	0.49	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.69
MutPred		0.57		Loss of catalytic residue at F156 (P = 0.0755);Loss of catalytic residue at F156 (P = 0.0755);.;
MVP		0.42
MPC		1.5
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs863224884; hg19: chr2-233635615;