1-119984359-C-T

Variant names:

• chr1-119984359-C-T
• rs1493694
• NM_024408.4:c.874+2601G>A

Variant summary

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

The NM_024408.4(NOTCH2):​c.874+2601G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,110 control chromosomes in the GnomAD database, including 5,855 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 0.22 (5855 hom., cov: 32)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.172
• Publications: 33 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.874+2601G>A		intron_variant	Intron 5 of 33	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.874+2601G>A		intron_variant	Intron 5 of 21		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.874+2601G>A		intron_variant	Intron 5 of 33	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.1012+2601G>A		intron_variant	Intron 4 of 13	1
NOTCH2	ENST00000640021.1	n.91+2601G>A		intron_variant	Intron 1 of 11	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32750 AN: 151992 Hom.: 5839 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.216 AC: 32792 AN: 152110 Hom.: 5855 Cov.: 32 AF XY: 0.213 AC XY: 15845 AN XY: 74364

African (AFR) AF: 0.491 AC: 20362 AN: 41458

American (AMR) AF: 0.125 AC: 1905 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

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

South Asian (SAS) AF: 0.190 AC: 916 AN: 4828

European-Finnish (FIN) AF: 0.135 AC: 1424 AN: 10586

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7192 AN: 67988

Other (OTH) AF: 0.189 AC: 400 AN: 2114

Alfa AF: 0.128 Hom.: 2404

Bravo AF: 0.224

Asia WGS AF: 0.174 AC: 605 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
DANN	Benign	0.64
PhyloP100		-0.17
Mutation Taster		=99/1	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: rs1493694; hg19: chr1-120526982;