rs699779

Variant names:

• chr1-119912687-A-G
• rs699779
• NM_024408.4:c.*2619T>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.*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
• Publications: 24 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=-0.56).
• 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 rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.*2619T>C		3_prime_UTR_variant	Exon 34 of 34	ENST00000256646.7	NP_077719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.*2619T>C		3_prime_UTR_variant	Exon 34 of 34	1	NM_024408.4	ENSP00000256646.2

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

African (AFR) AF: 0.354 AC: 1373 AN: 3882

American (AMR) AF: 0.113 AC: 283 AN: 2498

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 359 AN: 5122

East Asian (EAS) AF: 0.0172 AC: 195 AN: 11360

South Asian (SAS) AF: 0.186 AC: 130 AN: 698

European-Finnish (FIN) AF: 0.136 AC: 29 AN: 214

Middle Eastern (MID) AF: 0.0793 AC: 39 AN: 492

European-Non Finnish (NFE) AF: 0.102 AC: 5077 AN: 49978

Other (OTH) AF: 0.132 AC: 892 AN: 6770

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

African (AFR) AF: 0.338 AC: 14028 AN: 41480

American (AMR) AF: 0.108 AC: 1649 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3468

East Asian (EAS) AF: 0.0316 AC: 164 AN: 5190

South Asian (SAS) AF: 0.190 AC: 915 AN: 4818

European-Finnish (FIN) AF: 0.134 AC: 1425 AN: 10600

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7241 AN: 68020

Other (OTH) AF: 0.155 AC: 329 AN: 2116

Alfa AF: 0.135 Hom.: 1191

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
PhyloP100		0.034
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: rs699779; hg19: chr1-120455310;