rs835576

chr1-119912963-T-C

Variant summary

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

The NM_024408.4(NOTCH2):c.*2343A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 233,268 control chromosomes in the GnomAD database, including 3,901 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 (3270 hom., cov: 33)
  • Exomes 𝑓: 0.10 (631 hom.)
• Consequence: NOTCH2 NM_024408.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.26

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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.*2343A>G		3_prime_UTR_variant	34/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.*2343A>G		3_prime_UTR_variant	34/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26446 AN: 152034 Hom.: 3258 Cov.: 33

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.0320

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.104 AC: 8432 AN: 81116 Hom.: 631 Cov.: 0 AF XY: 0.101 AC XY: 3787 AN XY: 37326

Gnomad4 AFR exome AF: 0.361

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.0699

Gnomad4 EAS exome AF: 0.0171

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.174 AC: 26480 AN: 152152 Hom.: 3270 Cov.: 33 AF XY: 0.173 AC XY: 12894 AN XY: 74380

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.0317

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.158

Alfa AF: 0.114 Hom.: 1144

Bravo AF: 0.177

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.0040
Dann	Benign	0.41

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: rs835576; hg19: chr1-120455586; COSMIC: COSV56710987; COSMIC: COSV56710987;