rs699779

chr1-119912687-A-G

Variant summary

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

The NM_024408.4(NOTCH2):c.*2619T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 233,196 control chromosomes in the GnomAD database, including 3,788 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 (3165 hom., cov: 33)
  • Exomes 𝑓: 0.10 (623 hom.)
• Consequence: NOTCH2 NM_024408.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0340

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=-0.56).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.*2619T>C		3_prime_UTR_variant	34/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.*2619T>C		3_prime_UTR_variant	34/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26084 AN: 152064 Hom.: 3153 Cov.: 33

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.156

GnomAD4 exome AF: 0.103 AC: 8377 AN: 81014 Hom.: 623 Cov.: 0 AF XY: 0.101 AC XY: 3766 AN XY: 37242

Gnomad4 AFR exome AF: 0.354

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.0701

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.172 AC: 26118 AN: 152182 Hom.: 3165 Cov.: 33 AF XY: 0.171 AC XY: 12745 AN XY: 74406

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0316

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.155

Alfa AF: 0.135 Hom.: 809

Bravo AF: 0.174

Asia WGS AF: 0.165 AC: 573 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.5
Dann	Benign	0.89

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: rs699779; hg19: chr1-120455310;