2-8726921-A-C

Variant names:

• chr2-8726921-A-C
• rs1042842703
• NM_001348738.2:c.4019T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001348738.2(KIDINS220):​c.4019T>G​(p.Ile1340Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000176 in 1,136,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: KIDINS220 NM_001348738.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15577263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIDINS220	NM_001348738.2	c.4019T>G	p.Ile1340Arg	missense_variant	Exon 29 of 30		NP_001335667.1
KIDINS220	NM_001348739.2	c.3908T>G	p.Ile1303Arg	missense_variant	Exon 28 of 29		NP_001335668.1
KIDINS220	NM_001348740.2	c.3908T>G	p.Ile1303Arg	missense_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.3938T>G	p.Ile1313Arg	missense_variant	Exon 29 of 30			ENSP00000510537.1
KIDINS220	ENST00000689369.1	c.3905T>G	p.Ile1302Arg	missense_variant	Exon 28 of 29			ENSP00000509856.1
KIDINS220	ENST00000693394.1	c.3905T>G	p.Ile1302Arg	missense_variant	Exon 28 of 29			ENSP00000509014.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000743 AC: 1 AN: 134566 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73288

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000189

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000176 AC: 2 AN: 1136890 Hom.: 0 Cov.: 28 AF XY: 0.00000179 AC XY: 1 AN XY: 557820

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: 0.00000217

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.0047	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.98	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.041
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.016	D
MutPred		0.13		Loss of sheet (P = 0.0181);
MVP		0.34
ClinPred		0.36	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042842703; hg19: chr2-8867051;