2-8726914-GCTAT-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_ModeratePM2BS1_Supporting

The NM_001348738.2(KIDINS220):c.4022_4025delATAG(p.Asp1341AlafsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,288,946 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 1 hom. )

Consequence

KIDINS220
NM_001348738.2 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.16

Variant links:

Genes affected

KIDINS220 (HGNC:29508): (kinase D interacting substrate 220) This gene encodes a transmembrane protein that is preferentially expressed in the nervous system where it controls neuronal cell survival, differentiation into exons and dendrites, and synaptic plasticity. The encoded protein interacts with membrane receptors, cytosolic signaling components, and cytoskeletal proteins, serving as a scaffold that mediates crosstalk between the neurotrophin pathway and several other intracellular signaling pathways. Aberrant expression of this gene is associated with the onset of various neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease. Naturally occurring mutations in this gene are associated with a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

KIDINS220 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00618 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000105 (16/152294) while in subpopulation AMR AF= 0.00085 (13/15300). AF 95% confidence interval is 0.000502. There are 0 homozygotes in gnomad4. There are 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
KIDINS220	NM_001348738.2 link	c.4022_4025delATAG	p.Asp1341AlafsTer58	frameshift_variant	Exon 29 of 30	NP_001335667.1
KIDINS220	NM_001348739.2 link	c.3911_3914delATAG	p.Asp1304AlafsTer58	frameshift_variant	Exon 28 of 29	NP_001335668.1
KIDINS220	NM_001348740.2 link	c.3911_3914delATAG	p.Asp1304AlafsTer18	frameshift_variant	Exon 28 of 29	NP_001335669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
KIDINS220	ENST00000689852.1 link	c.3941_3944delATAG	p.Asp1314AlafsTer58	frameshift_variant	Exon 29 of 30	ENSP00000510537.1	A0A8I5QL22
KIDINS220	ENST00000689369.1 link	c.3908_3911delATAG	p.Asp1303AlafsTer15	frameshift_variant	Exon 28 of 29	ENSP00000509856.1	A0A8I5QJC0
KIDINS220	ENST00000693394.1 link	c.3908_3911delATAG	p.Asp1303AlafsTer18	frameshift_variant	Exon 28 of 29	ENSP00000509014.1	A0A8I5QJC0

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000156

AC:

AN:

134564

Hom.:

AF XY:

0.000109

AC XY:

AN XY:

73288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000777

Gnomad ASJ exome

AF:

0.000121

Gnomad EAS exome

AF:

0.0000952

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1136652

Hom.:

AF XY:

0.0000233

AC XY:

AN XY:

557734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000637

Gnomad4 ASJ exome

AF:

0.0000628

Gnomad4 EAS exome

AF:

0.000156

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000870

Gnomad4 OTH exome

AF:

0.0000241

GnomAD4 genome

AF:

0.000105

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000208

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KIDINS220-related disorder

Uncertain:1

Aug 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KIDINS220 c.3908_3911delATAG variant is predicted to result in a frameshift and premature protein termination (p.Asp1303Alafs*15). Of note, this variant is designated c.*3802_*3805del (post-coding) in another transcript (NM_020738.4). To our knowledge, this variant has not been reported in the literature and it is unclear if a frameshift variant in this transcript would be expected to cause disease. This variant is reported in 0.078% of alleles in individuals of Latino descent in gnomAD, including one homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over