rs2453051

Variant names:

• chr1-119956950-A-C
• rs2453051
• NM_024408.4:c.2027-1718T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024408.4(NOTCH2):​c.2027-1718T>G 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 152,082 control chromosomes in the GnomAD database, including 2,895 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 (2895 hom., cov: 32)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• Publications: 12 publications found

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]

NOTCH2 Gene-Disease associations (from GenCC):

• acroosteolysis dominant type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Alagille syndrome due to a NOTCH2 point mutation

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Alagille syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• 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 rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.2027-1718T>G		intron_variant	Intron 12 of 33	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.2027-1718T>G		intron_variant	Intron 12 of 21		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.2027-1718T>G		intron_variant	Intron 12 of 33	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.2165-1718T>G		intron_variant	Intron 11 of 13	1
NOTCH2	ENST00000640021.1	n.*1151-1718T>G		intron_variant	Intron 9 of 11	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25328 AN: 151964 Hom.: 2884 Cov.: 32

Gnomad AFR AF: 0.322

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: 25360 AN: 152082 Hom.: 2895 Cov.: 32 AF XY: 0.167 AC XY: 12385 AN XY: 74356

African (AFR) AF: 0.322 AC: 13347 AN: 41392

American (AMR) AF: 0.107 AC: 1631 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3470

East Asian (EAS) AF: 0.0316 AC: 164 AN: 5190

South Asian (SAS) AF: 0.189 AC: 915 AN: 4830

European-Finnish (FIN) AF: 0.133 AC: 1410 AN: 10580

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7196 AN: 68002

Other (OTH) AF: 0.156 AC: 330 AN: 2114

Alfa AF: 0.142 Hom.: 238

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	-0.99
CADD	Benign	4.6
DANN	Benign	0.62
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2453051; hg19: chr1-120499573;