2-232765966-C-T

Variant names:

• chr2-232765966-C-T
• rs77237820
• NM_002242.4:c.*2225G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002242.4(KCNJ13):​c.*2225G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0359 in 466,168 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (100 hom., cov: 32)
  • Exomes 𝑓: 0.037 (292 hom.)
• Consequence: KCNJ13 NM_002242.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0170

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]

ENSG00000241409 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-232765966-C-T is Benign according to our data. Variant chr2-232765966-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 898161.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0326 (4806/147474) while in subpopulation NFE AF= 0.0493 (3265/66282). AF 95% confidence interval is 0.0478. There are 100 homozygotes in gnomad4. There are 2232 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 100 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ13	NM_002242.4	c.*2225G>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000233826.4	NP_002233.2
GIGYF2	NM_001103146.3	c.532+4530C>T		intron_variant	Intron 8 of 28	ENST00000373563.9	NP_001096616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ13	ENST00000233826	c.*2225G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_002242.4	ENSP00000233826.3
GIGYF2	ENST00000373563.9	c.532+4530C>T		intron_variant	Intron 8 of 28	1	NM_001103146.3	ENSP00000362664.5

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4806 AN: 147358 Hom.: 100 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0755

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0584

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0259

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.0324

GnomAD3 exomes AF: 0.0329 AC: 4909 AN: 149074 Hom.: 106 AF XY: 0.0346 AC XY: 2777 AN XY: 80296

Gnomad AFR exome AF: 0.00962

Gnomad AMR exome AF: 0.0197

Gnomad ASJ exome AF: 0.0602

Gnomad EAS exome AF: 0.000278

Gnomad SAS exome AF: 0.0309

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0482

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0375 AC: 11939 AN: 318694 Hom.: 292 Cov.: 0 AF XY: 0.0382 AC XY: 6882 AN XY: 180052

Gnomad4 AFR exome AF: 0.00904

Gnomad4 AMR exome AF: 0.0197

Gnomad4 ASJ exome AF: 0.0573

Gnomad4 EAS exome AF: 0.000217

Gnomad4 SAS exome AF: 0.0311

Gnomad4 FIN exome AF: 0.0199

Gnomad4 NFE exome AF: 0.0482

Gnomad4 OTH exome AF: 0.0377

GnomAD4 genome AF: 0.0326 AC: 4806 AN: 147474 Hom.: 100 Cov.: 32 AF XY: 0.0310 AC XY: 2232 AN XY: 71902

Gnomad4 AFR AF: 0.0113

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.0584

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0259

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.0493

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0430 Hom.: 59

Bravo AF: 0.0298

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leber congenital amaurosis 16 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.6
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs77237820; hg19: chr2-233630676;