dbSNP rs77237820: KCNJ13:c.*2225G>A (chr2-232765966-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0170

Publications

1 publications found

Variant links:

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]

KCNJ13 links:

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

GIGYF2 links:

ENSG00000241409 (HGNC:):

ENSG00000241409 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 100 AR,AD gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNJ13	NM_002242.4	MANE Select	c.*2225G>A	3_prime_UTR	Exon 3 of 3	NP_002233.2	O60928-1
GIGYF2	NM_001103146.3	MANE Select	c.532+4530C>T	intron	N/A	NP_001096616.1	Q6Y7W6-1
KCNJ13	NM_001172417.1		c.*2225G>A	3_prime_UTR	Exon 3 of 3	NP_001165888.1	O60928

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
KCNJ13	ENST00000233826.4	TSL:1 MANE Select	c.*2225G>A	3_prime_UTR	Exon 3 of 3	ENSP00000233826.3	O60928-1
GIGYF2	ENST00000373563.9	TSL:1 MANE Select	c.532+4530C>T	intron	N/A	ENSP00000362664.5	Q6Y7W6-1
GIGYF2	ENST00000409451.7	TSL:1	c.532+4530C>T	intron	N/A	ENSP00000387170.3	Q6Y7W6-3

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

4806

AN:

147358

Hom.:

100

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0329

AC:

4909

AN:

149074

AF XY:

0.0346

show subpopulations

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 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.:

AF XY:

0.0382

AC XY:

6882

AN XY:

180052

show subpopulations

African (AFR)

AF:

0.00904

AC:

AN:

8632

American (AMR)

AF:

0.0197

AC:

537

AN:

27280

Ashkenazi Jewish (ASJ)

AF:

0.0573

AC:

618

AN:

10780

East Asian (EAS)

AF:

0.000217

AC:

AN:

9214

South Asian (SAS)

AF:

0.0311

AC:

1857

AN:

59706

European-Finnish (FIN)

AF:

0.0199

AC:

538

AN:

27060

Middle Eastern (MID)

AF:

0.0406

AC:

113

AN:

2784

European-Non Finnish (NFE)

AF:

0.0482

AC:

7656

AN:

158924

Other (OTH)

AF:

0.0377

AC:

540

AN:

14314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.426

Heterozygous variant carriers

602

1205

1807

2410

3012

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0326

AC:

4806

AN:

147474

Hom.:

100

Cov.:

AF XY:

0.0310

AC XY:

2232

AN XY:

71902

show subpopulations

African (AFR)

AF:

0.0113

AC:

458

AN:

40434

American (AMR)

AF:

0.0272

AC:

389

AN:

14316

Ashkenazi Jewish (ASJ)

AF:

0.0584

AC:

197

AN:

3372

East Asian (EAS)

AF:

0.00

AC:

AN:

5038

South Asian (SAS)

AF:

0.0259

AC:

121

AN:

4666

European-Finnish (FIN)

AF:

0.0235

AC:

238

AN:

10144

Middle Eastern (MID)

AF:

0.0207

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0493

AC:

3265

AN:

66282

Other (OTH)

AF:

0.0321

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

239

479

718

958

1197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0443

Hom.:

273

Bravo

AF:

0.0298

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Leber congenital amaurosis 16 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.6

(source)

DANN

Benign

0.77

PhyloP100

0.017

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over