2-8726897-T-C

Position:

chr2-8726897-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM2PP2BP4_StrongBP6BS1

The NM_001348738.2(KIDINS220):c.4043A>G(p.Asp1348Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,288,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KIDINS220
NM_001348738.2 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.00200

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 Likely_benign. Variant got -6 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 3.3791 (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=0.005635202).

BP6

Variant 2-8726897-T-C is Benign according to our data. Variant chr2-8726897-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3051329.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000282 (43/152346) while in subpopulation EAS AF= 0.00771 (40/5188). AF 95% confidence interval is 0.00582. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
KIDINS220	NM_001348738.2 linkuse as main transcript	c.4043A>G	p.Asp1348Gly	missense_variant	29/30	NP_001335667.1
KIDINS220	NM_001348739.2 linkuse as main transcript	c.3932A>G	p.Asp1311Gly	missense_variant	28/29	NP_001335668.1
KIDINS220	NM_001348740.2 linkuse as main transcript	c.3932A>G	p.Asp1311Gly	missense_variant	28/29	NP_001335669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	Protein
KIDINS220	ENST00000689852.1 linkuse as main transcript	c.3962A>G	p.Asp1321Gly	missense_variant	29/30	ENSP00000510537
KIDINS220	ENST00000689369.1 linkuse as main transcript	c.3929A>G	p.Asp1310Gly	missense_variant	28/29	ENSP00000509856
KIDINS220	ENST00000693394.1 linkuse as main transcript	c.3929A>G	p.Asp1310Gly	missense_variant	28/29	ENSP00000509014

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00750

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000818

AC:

110

AN:

134552

Hom.:

AF XY:

0.000723

AC XY:

AN XY:

73288

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00942

Gnomad SAS exome

AF:

0.000445

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000241

GnomAD4 exome

AF:

0.000124

AC:

141

AN:

1136350

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

557562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00795

Gnomad4 SAS exome

AF:

0.000249

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000217

Gnomad4 OTH exome

AF:

0.000434

GnomAD4 genome

AF:

0.000282

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00771

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.000453

ExAC

AF:

0.000195

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KIDINS220-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0050

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.97

PROVEAN

Benign

-0.60

REVEL

Benign

0.060

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

MVP

0.19

ClinPred

0.036

GERP RS

-0.85

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