1-119913940-G-T

Position:

• chr1-119913940-G-T

Variant summary

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

The ENST00000256646.7(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 ENST00000256646.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420

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=-0.89).
• 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/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.*1366C>A		3_prime_UTR_variant	34/34	ENST00000256646.7	NP_077719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.*1366C>A		3_prime_UTR_variant	34/34	1	NM_024408.4	ENSP00000256646	P1

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

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.0692

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.130

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

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0824

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.190

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.156

Alfa AF: 0.112 Hom.: 2003

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

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: rs835575; hg19: chr1-120456563;