2-8730732-T-C

Variant names:

• chr2-8730732-T-C
• rs13406422
• NM_020738.4:c.5304A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_020738.4(KIDINS220):​c.5304A>G​(p.Glu1768Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,612,648 control chromosomes in the GnomAD database, including 3,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (344 hom., cov: 32)
  • Exomes 𝑓: 0.019 (2679 hom.)
• Consequence: KIDINS220 NM_020738.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0450
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• ventriculomegaly and arthrogryposis

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• spastic paraplegia, intellectual disability, nystagmus, and obesity

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-8730732-T-C is Benign according to our data. Variant chr2-8730732-T-C is described in ClinVar as Benign. ClinVar VariationId is 1166247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.045 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020738.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIDINS220	NM_020738.4	MANE Select	c.5304A>G	p.Glu1768Glu	synonymous	Exon 30 of 30	NP_065789.1	Q9ULH0-1
	KIDINS220	NM_001348729.2		c.5307A>G	p.Glu1769Glu	synonymous	Exon 30 of 30	NP_001335658.1
	KIDINS220	NM_001348731.2		c.5250A>G	p.Glu1750Glu	synonymous	Exon 29 of 29	NP_001335660.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIDINS220	ENST00000256707.8	TSL:1 MANE Select	c.5304A>G	p.Glu1768Glu	synonymous	Exon 30 of 30	ENSP00000256707.4	Q9ULH0-1
	KIDINS220	ENST00000488729.5	TSL:1	n.*5193A>G		non_coding_transcript_exon	Exon 29 of 29	ENSP00000417390.1	F8WAY8
	KIDINS220	ENST00000488729.5	TSL:1	n.*5193A>G		3_prime_UTR	Exon 29 of 29	ENSP00000417390.1	F8WAY8

Frequencies

GnomAD3 genomes AF: 0.0249 AC: 3791 AN: 152230 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0895

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0514 AC: 12764 AN: 248314 AF XY: 0.0459

Gnomad AFR exome AF: 0.00362

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.00470

Gnomad EAS exome AF: 0.274

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.00272

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0190 AC: 27748 AN: 1460300 Hom.: 2679 Cov.: 37 AF XY: 0.0191 AC XY: 13911 AN XY: 726488

African (AFR) AF: 0.00229 AC: 76 AN: 33250

American (AMR) AF: 0.151 AC: 6678 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 92 AN: 26072

East Asian (EAS) AF: 0.301 AC: 11946 AN: 39692

South Asian (SAS) AF: 0.0504 AC: 4333 AN: 86056

European-Finnish (FIN) AF: 0.0124 AC: 661 AN: 53348

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5756

European-Non Finnish (NFE) AF: 0.00203 AC: 2256 AN: 1111494

Other (OTH) AF: 0.0279 AC: 1682 AN: 60280

GnomAD4 genome AF: 0.0251 AC: 3818 AN: 152348 Hom.: 344 Cov.: 32 AF XY: 0.0282 AC XY: 2100 AN XY: 74486

African (AFR) AF: 0.00365 AC: 152 AN: 41590

American (AMR) AF: 0.0900 AC: 1377 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.299 AC: 1547 AN: 5176

South Asian (SAS) AF: 0.0620 AC: 299 AN: 4826

European-Finnish (FIN) AF: 0.0154 AC: 164 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 68034

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

Alfa AF: 0.00599 Hom.: 21

Bravo AF: 0.0319

Asia WGS AF: 0.174 AC: 605 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.97
DANN	Benign	0.46
PhyloP100		-0.045
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs13406422; hg19: chr2-8870862; COSMIC: COSV56751556; COSMIC: COSV56751556;