2-8726894-T-C

Variant names:

• chr2-8726894-T-C
• rs1317199300
• NM_001348738.2:c.4046A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_001348738.2(KIDINS220):​c.4046A>G​(p.Ter1349Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000088 in 1,136,108 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 Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: KIDINS220 NM_001348738.2 stop_retained
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-8726894-T-C is Benign according to our data. Variant chr2-8726894-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3353437.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIDINS220	NM_001348738.2	c.4046A>G	p.Ter1349Ter	stop_retained_variant	Exon 29 of 30		NP_001335667.1
KIDINS220	NM_001348739.2	c.3935A>G	p.Ter1312Ter	stop_retained_variant	Exon 28 of 29		NP_001335668.1
KIDINS220	NM_001348740.2	c.3935A>G	p.Ter1312Ter	stop_retained_variant	Exon 28 of 29		NP_001335669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIDINS220	ENST00000689852.1	c.3965A>G	p.Ter1322Ter	stop_retained_variant	Exon 29 of 30			ENSP00000510537.1
KIDINS220	ENST00000689369.1	c.3932A>G	p.Ter1311Ter	stop_retained_variant	Exon 28 of 29			ENSP00000509856.1
KIDINS220	ENST00000693394.1	c.3932A>G	p.Ter1311Ter	stop_retained_variant	Exon 28 of 29			ENSP00000509014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.80e-7 AC: 1 AN: 1136108 Hom.: 0 Cov.: 28 AF XY: 0.00000179 AC XY: 1 AN XY: 557456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KIDINS220-related disorder Benign:1

Aug 05, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1317199300; hg19: chr2-8867024;