NM_001348738.2:c.4046A>G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 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: Likely_benign. The variant received -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 VariationId is 3353437.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348738.2. 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_001348738.2		c.4046A>G	p.Ter1349Ter	stop_retained	Exon 29 of 30	NP_001335667.1
	KIDINS220	NM_001348739.2		c.3935A>G	p.Ter1312Ter	stop_retained	Exon 28 of 29	NP_001335668.1
	KIDINS220	NM_001348740.2		c.3935A>G	p.Ter1312Ter	stop_retained	Exon 28 of 29	NP_001335669.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIDINS220	ENST00000689852.1		c.3965A>G	p.Ter1322Ter	stop_retained	Exon 29 of 30	ENSP00000510537.1	A0A8I5QL22
	KIDINS220	ENST00000689369.1		c.3932A>G	p.Ter1311Ter	stop_retained	Exon 28 of 29	ENSP00000509856.1	A0A8I5QJC0
	KIDINS220	ENST00000693394.1		c.3932A>G	p.Ter1311Ter	stop_retained	Exon 28 of 29	ENSP00000509014.1	A0A8I5QJC0

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

African (AFR) AF: 0.00 AC: 0 AN: 24390

American (AMR) AF: 0.00 AC: 0 AN: 28264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15938

East Asian (EAS) AF: 0.00 AC: 0 AN: 12836

South Asian (SAS) AF: 0.00 AC: 0 AN: 76168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13068

Middle Eastern (MID) AF: 0.000227 AC: 1 AN: 4402

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 919564

Other (OTH) AF: 0.00 AC: 0 AN: 41478

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KIDINS220-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.76
PhyloP100		1.2

Splicing

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

Other links and lift over

dbSNP: rs1317199300; hg19: chr2-8867024;