1-119912818-A-G

Position:

• chr1-119912818-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.*2488T>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 0.255 in 233,320 control chromosomes in the GnomAD database, including 14,524 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 0.31 (12697 hom., cov: 33)
  • Exomes 𝑓: 0.15 (1827 hom.)
• Consequence: NOTCH2 NM_024408.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.424

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.*2488T>C		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.*2488T>C		3_prime_UTR_variant	34/34	1	NM_024408.4	ENSP00000256646	P1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46911 AN: 151998 Hom.: 12644 Cov.: 33

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0986

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.155 AC: 12580 AN: 81204 Hom.: 1827 Cov.: 0 AF XY: 0.151 AC XY: 5658 AN XY: 37372

Gnomad4 AFR exome AF: 0.742

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.0443

Gnomad4 SAS exome AF: 0.303

Gnomad4 FIN exome AF: 0.189

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.309 AC: 47028 AN: 152116 Hom.: 12697 Cov.: 33 AF XY: 0.308 AC XY: 22930 AN XY: 74392

Gnomad4 AFR AF: 0.734

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.0982

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.269

Alfa AF: 0.152 Hom.: 2970

Bravo AF: 0.326

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.83
DANN	Benign	0.53

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: rs699780; hg19: chr1-120455441; COSMIC: COSV56710977; COSMIC: COSV56710977;