2-232765867-G-A

Position:

• chr2-232765867-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_002242.4(KCNJ13):​c.*2324C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 464,662 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (8 hom., cov: 33)
  • Exomes 𝑓: 0.012 (51 hom.)
• Consequence: KCNJ13 NM_002242.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.142

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1692/152244) while in subpopulation NFE AF= 0.0167 (1133/68020). AF 95% confidence interval is 0.0159. There are 8 homozygotes in gnomad4. There are 787 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ13	NM_002242.4	c.*2324C>T		3_prime_UTR_variant	3/3	ENST00000233826.4
GIGYF2	NM_001103146.3	c.532+4431G>A		intron_variant		ENST00000373563.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ13	ENST00000233826.4	c.*2324C>T		3_prime_UTR_variant	3/3	1	NM_002242.4	P1
GIGYF2	ENST00000373563.9	c.532+4431G>A		intron_variant		1	NM_001103146.3	P4
	ENST00000427571.1	n.271+1812C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1693 AN: 152126 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0144

GnomAD4 exome AF: 0.0122 AC: 3799 AN: 312418 Hom.: 51 Cov.: 0 AF XY: 0.0112 AC XY: 1964 AN XY: 176120

Gnomad4 AFR exome AF: 0.00357

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.000110

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00918

Gnomad4 NFE exome AF: 0.0178

Gnomad4 OTH exome AF: 0.0129

GnomAD4 genome AF: 0.0111 AC: 1692 AN: 152244 Hom.: 8 Cov.: 33 AF XY: 0.0106 AC XY: 787 AN XY: 74452

Gnomad4 AFR AF: 0.00318

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00962

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0133 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Leber congenital amaurosis 16 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.2
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs74547374; hg19: chr2-233630577;