2-8726914-GCTAT-G

Variant names:

• chr2-8726914-GCTAT-G
• rs1233193294
• NM_001348738.2:c.4022_4025delATAG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PVS1_Moderate PM2 BS1_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
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.16

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 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	MANE	Protein	UniProt
KIDINS220	NM_001348738.2	c.4022_4025delATAG	p.Asp1341AlafsTer58	frameshift_variant	Exon 29 of 30		NP_001335667.1
KIDINS220	NM_001348739.2	c.3911_3914delATAG	p.Asp1304AlafsTer58	frameshift_variant	Exon 28 of 29		NP_001335668.1
KIDINS220	NM_001348740.2	c.3911_3914delATAG	p.Asp1304AlafsTer18	frameshift_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.3941_3944delATAG	p.Asp1314AlafsTer58	frameshift_variant	Exon 29 of 30			ENSP00000510537.1
KIDINS220	ENST00000689369.1	c.3908_3911delATAG	p.Asp1303AlafsTer15	frameshift_variant	Exon 28 of 29			ENSP00000509856.1
KIDINS220	ENST00000693394.1	c.3908_3911delATAG	p.Asp1303AlafsTer18	frameshift_variant	Exon 28 of 29			ENSP00000509014.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152176 Hom.: 0 Cov.: 33

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: 21 AN: 134564 Hom.: 1 AF XY: 0.000109 AC XY: 8 AN XY: 73288

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: 30 AN: 1136652 Hom.: 1 AF XY: 0.0000233 AC XY: 13 AN XY: 557734

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: 16 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74478

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

Submissions by phenotype

KIDINS220-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2024

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1233193294; hg19: chr2-8867044;