rs1801251

Variant names:

• chr2-232768750-G-A
• rs1801251
• NM_002242.4:c.524C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-232768750-G-A
• chr2-232768750-G-C
• chr2-232768750-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002242.4(KCNJ13):​c.524C>T​(p.Thr175Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,600,060 control chromosomes in the GnomAD database, including 107,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T175R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (7983 hom., cov: 32)
  • Exomes 𝑓: 0.36 (99303 hom.)
• Consequence: KCNJ13 NM_002242.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.38
• Publications: 49 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.492368E-5).
• BP6: Variant 2-232768750-G-A is Benign according to our data. Variant chr2-232768750-G-A is described in ClinVar as Benign. ClinVar VariationId is 335056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.604 is higher than 0.05.

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.524C>T	p.Thr175Ile	missense	Exon 3 of 3	NP_002233.2	O60928-1
	GIGYF2	NM_001103146.3	MANE Select	c.532+7314G>A		intron	N/A	NP_001096616.1	Q6Y7W6-1
	KCNJ13	NM_001172417.1		c.284C>T	p.Thr95Ile	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.524C>T	p.Thr175Ile	missense	Exon 3 of 3	ENSP00000233826.3	O60928-1
	KCNJ13	ENST00000410029.1	TSL:1	c.524C>T	p.Thr175Ile	missense	Exon 2 of 2	ENSP00000386251.1	O60928-1
	GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.532+7314G>A		intron	N/A	ENSP00000362664.5	Q6Y7W6-1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48115 AN: 151930 Hom.: 7974 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.335

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.349 AC: 86796 AN: 248762 AF XY: 0.367

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.337

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.340

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.361 AC: 523334 AN: 1448012 Hom.: 99303 Cov.: 34 AF XY: 0.370 AC XY: 265308 AN XY: 717456

African (AFR) AF: 0.270 AC: 8943 AN: 33146

American (AMR) AF: 0.255 AC: 11230 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 8564 AN: 25890

East Asian (EAS) AF: 0.291 AC: 11440 AN: 39334

South Asian (SAS) AF: 0.627 AC: 53722 AN: 85644

European-Finnish (FIN) AF: 0.239 AC: 12738 AN: 53244

Middle Eastern (MID) AF: 0.431 AC: 2452 AN: 5688

European-Non Finnish (NFE) AF: 0.356 AC: 392454 AN: 1101352

Other (OTH) AF: 0.365 AC: 21791 AN: 59742

GnomAD4 genome AF: 0.317 AC: 48139 AN: 152048 Hom.: 7983 Cov.: 32 AF XY: 0.316 AC XY: 23460 AN XY: 74298

African (AFR) AF: 0.266 AC: 11030 AN: 41492

American (AMR) AF: 0.290 AC: 4432 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 1162 AN: 3470

East Asian (EAS) AF: 0.332 AC: 1716 AN: 5166

South Asian (SAS) AF: 0.622 AC: 3001 AN: 4824

European-Finnish (FIN) AF: 0.237 AC: 2502 AN: 10556

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23185 AN: 67938

Other (OTH) AF: 0.318 AC: 672 AN: 2114

Alfa AF: 0.335 Hom.: 33696

Bravo AF: 0.309

TwinsUK AF: 0.361 AC: 1337

ALSPAC AF: 0.357 AC: 1377

ESP6500AA AF: 0.265 AC: 1166

ESP6500EA AF: 0.350 AC: 3013

ExAC AF: 0.354 AC: 43007

Asia WGS AF: 0.493 AC: 1712 AN: 3478

EpiCase AF: 0.347

EpiControl AF: 0.344

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Leber congenital amaurosis 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	11
DANN	Benign	0.77
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.013	T
MetaRNN	Benign	0.000075	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.41	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.55
ClinPred		0.0062	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs1801251; hg19: chr2-233633460; COSMIC: COSV52084781; COSMIC: COSV52084781;