2-8726914-GCTAT-G
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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_4025del(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
NM_001348738.2 frameshift
Scores
Not classified
Clinical Significance
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]
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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/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KIDINS220 | NM_001348738.2 | c.4022_4025del | p.Asp1341AlafsTer58 | frameshift_variant | 29/30 | NP_001335667.1 | ||
| KIDINS220 | NM_001348739.2 | c.3911_3914del | p.Asp1304AlafsTer58 | frameshift_variant | 28/29 | NP_001335668.1 | ||
| KIDINS220 | NM_001348740.2 | c.3911_3914del | p.Asp1304AlafsTer18 | frameshift_variant | 28/29 | NP_001335669.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KIDINS220 | ENST00000496383.5 | c.3149_3152del | p.Asp1050AlafsTer? | frameshift_variant | 21/22 | 5 | ENSP00000420364 | |||
| KIDINS220 | ENST00000689369.1 | c.3908_3911del | p.Asp1303AlafsTer15 | frameshift_variant | 28/29 | ENSP00000509856 | ||||
| KIDINS220 | ENST00000689852.1 | c.3941_3944del | p.Asp1314AlafsTer58 | frameshift_variant | 29/30 | ENSP00000510537 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152176Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000156 AC: 21AN: 134564Hom.: 1 AF XY: 0.000109 AC XY: 8AN XY: 73288
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GnomAD4 exome AF: 0.0000264 AC: 30AN: 1136652Hom.: 1 AF XY: 0.0000233 AC XY: 13AN XY: 557734
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GnomAD4 genome 0.000105 AC: 16AN: 152294Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74478
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link
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. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at