rs2493413

chr1-119956951-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024408.4(NOTCH2):c.2027-1719C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 152,038 control chromosomes in the GnomAD database, including 2,894 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.17 (2894 hom., cov: 32)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.135

Genes affected

NOTCH2 (HGNC:7882): (notch receptor 2) This gene encodes a member of the Notch family. Members of this Type 1 transmembrane protein family share structural characteristics including an extracellular domain consisting of multiple epidermal growth factor-like (EGF) repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions. The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between physically adjacent cells. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signaling pathway that plays a key role in development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remain to be determined. This protein is cleaved in the trans-Golgi network, and presented on the cell surface as a heterodimer. This protein functions as a receptor for membrane bound ligands, and may play a role in vascular, renal and hepatic development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.2027-1719C>T		intron_variant		ENST00000256646.7
NOTCH2	NM_001200001.2	c.2027-1719C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.2027-1719C>T		intron_variant		1	NM_024408.4	P1
NOTCH2	ENST00000479412.2	n.2165-1719C>T		intron_variant, non_coding_transcript_variant		1
NOTCH2	ENST00000640021.1	c.*1151-1719C>T		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25329 AN: 151920 Hom.: 2883 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.157

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.167 AC: 25361 AN: 152038 Hom.: 2894 Cov.: 32 AF XY: 0.167 AC XY: 12384 AN XY: 74322

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.107

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.156

Alfa AF: 0.142 Hom.: 234

Bravo AF: 0.169

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	4.0
Dann	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs2493413; hg19: chr1-120499574;