chr2-8730781-A-C

Position:

chr2-8730781-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_020738.4(KIDINS220):c.5255T>G(p.Leu1752Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KIDINS220
NM_020738.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 8.20

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIDINS220. . Gene score misZ 2.2613 (greater than the threshold 3.09). Trascript score misZ 3.5585 (greater than threshold 3.09). GenCC has associacion of gene with spastic paraplegia, intellectual disability, nystagmus, and obesity, ventriculomegaly and arthrogryposis.

BP4

Computational evidence support a benign effect (MetaRNN=0.3833447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIDINS220	NM_020738.4 linkuse as main transcript	c.5255T>G	p.Leu1752Arg	missense_variant	30/30	ENST00000256707.8	NP_065789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIDINS220	ENST00000256707.8 linkuse as main transcript	c.5255T>G	p.Leu1752Arg	missense_variant	30/30	1	NM_020738.4	ENSP00000256707		Q9ULH0-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249558

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.00000752

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.00000827

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with KIDINS220-related conditions. This variant is present in population databases (rs772060146, gnomAD 0.008%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1752 of the KIDINS220 protein (p.Leu1752Arg). -

KIDINS220-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 27, 2024

The KIDINS220 c.5255T>G variant is predicted to result in the amino acid substitution p.Leu1752Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0083% of alleles in individuals of African descent in gnomAD. 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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.38

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.0

L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

1.0

D;.

Vest4

0.58

MutPred

0.18

Gain of helix (P = 0.0425);.;

MVP

0.76

MPC

0.97

ClinPred

0.62

GERP RS

5.7

Varity_R

0.62

gMVP

0.65

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

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