rs835575

Variant names:

• chr1-119913940-G-T
• rs835575
• NM_024408.4:c.*1366C>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.*1366C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 232,728 control chromosomes in the GnomAD database, including 3,567 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 (2974 hom., cov: 33)
  • Exomes 𝑓: 0.10 (593 hom.)
• Consequence: NOTCH2 NM_024408.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• Publications: 28 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.*1366C>A		3_prime_UTR_variant	Exon 34 of 34	ENST00000256646.7	NP_077719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.*1366C>A		3_prime_UTR_variant	Exon 34 of 34	1	NM_024408.4	ENSP00000256646.2

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25529 AN: 152012 Hom.: 2963 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0824

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.157

GnomAD4 exome AF: 0.102 AC: 8250 AN: 80598 Hom.: 593 Cov.: 0 AF XY: 0.100 AC XY: 3711 AN XY: 37072

African (AFR) AF: 0.343 AC: 1329 AN: 3876

American (AMR) AF: 0.113 AC: 280 AN: 2486

Ashkenazi Jewish (ASJ) AF: 0.0692 AC: 353 AN: 5098

East Asian (EAS) AF: 0.0172 AC: 195 AN: 11346

South Asian (SAS) AF: 0.178 AC: 124 AN: 698

European-Finnish (FIN) AF: 0.138 AC: 8 AN: 58

Middle Eastern (MID) AF: 0.0802 AC: 39 AN: 486

European-Non Finnish (NFE) AF: 0.101 AC: 5045 AN: 49794

Other (OTH) AF: 0.130 AC: 877 AN: 6756

GnomAD4 genome AF: 0.168 AC: 25561 AN: 152130 Hom.: 2974 Cov.: 33 AF XY: 0.168 AC XY: 12459 AN XY: 74378

African (AFR) AF: 0.326 AC: 13502 AN: 41456

American (AMR) AF: 0.106 AC: 1627 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0824 AC: 286 AN: 3472

East Asian (EAS) AF: 0.0315 AC: 163 AN: 5182

South Asian (SAS) AF: 0.190 AC: 914 AN: 4822

European-Finnish (FIN) AF: 0.135 AC: 1427 AN: 10586

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

European-Non Finnish (NFE) AF: 0.106 AC: 7235 AN: 68016

Other (OTH) AF: 0.156 AC: 329 AN: 2110

Alfa AF: 0.127 Hom.: 4447

Bravo AF: 0.170

Asia WGS AF: 0.166 AC: 576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.87
DANN	Benign	0.55
PhyloP100		0.042
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: rs835575; hg19: chr1-120456563;