1-119912818-A-G

Variant names:

• chr1-119912818-A-G
• rs699780
• NM_024408.4:c.*2488T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	NM_024408.4	MANE Select	c.*2488T>C		3_prime_UTR	Exon 34 of 34	NP_077719.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.*2488T>C		3_prime_UTR	Exon 34 of 34	ENSP00000256646.2

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

African (AFR) AF: 0.742 AC: 2883 AN: 3888

American (AMR) AF: 0.205 AC: 511 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 676 AN: 5118

East Asian (EAS) AF: 0.0443 AC: 503 AN: 11358

South Asian (SAS) AF: 0.303 AC: 212 AN: 700

European-Finnish (FIN) AF: 0.189 AC: 89 AN: 472

Middle Eastern (MID) AF: 0.173 AC: 85 AN: 490

European-Non Finnish (NFE) AF: 0.124 AC: 6208 AN: 49922

Other (OTH) AF: 0.209 AC: 1413 AN: 6760

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

African (AFR) AF: 0.734 AC: 30428 AN: 41458

American (AMR) AF: 0.196 AC: 2989 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 485 AN: 3466

East Asian (EAS) AF: 0.0982 AC: 509 AN: 5182

South Asian (SAS) AF: 0.313 AC: 1506 AN: 4818

European-Finnish (FIN) AF: 0.165 AC: 1750 AN: 10580

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8686 AN: 68012

Other (OTH) AF: 0.269 AC: 569 AN: 2116

Alfa AF: 0.179 Hom.: 5765

Bravo AF: 0.326

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.83
DANN	Benign	0.53
PhyloP100		-0.42
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: rs699780; hg19: chr1-120455441; COSMIC: COSV56710977; COSMIC: COSV56710977;