1-119912963-T-C

Variant names:

• chr1-119912963-T-C
• rs835576
• NM_024408.4:c.*2343A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 29 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Alagille syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, ClinGen
• Alagille syndrome due to a NOTCH2 point mutation

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	NM_024408.4	MANE Select	c.*2343A>G		3_prime_UTR	Exon 34 of 34	NP_077719.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.*2343A>G		3_prime_UTR	Exon 34 of 34	ENSP00000256646.2	Q04721
	NOTCH2	ENST00000924185.1		c.*2343A>G		3_prime_UTR	Exon 34 of 34	ENSP00000594244.1
	NOTCH2	ENST00000924186.1		c.*2343A>G		3_prime_UTR	Exon 32 of 32	ENSP00000594245.1

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

African (AFR) AF: 0.361 AC: 1400 AN: 3882

American (AMR) AF: 0.115 AC: 286 AN: 2490

Ashkenazi Jewish (ASJ) AF: 0.0699 AC: 357 AN: 5108

East Asian (EAS) AF: 0.0171 AC: 195 AN: 11372

South Asian (SAS) AF: 0.178 AC: 124 AN: 698

European-Finnish (FIN) AF: 0.137 AC: 59 AN: 432

Middle Eastern (MID) AF: 0.0796 AC: 39 AN: 490

European-Non Finnish (NFE) AF: 0.102 AC: 5075 AN: 49890

Other (OTH) AF: 0.133 AC: 897 AN: 6754

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

African (AFR) AF: 0.346 AC: 14361 AN: 41502

American (AMR) AF: 0.109 AC: 1670 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3470

East Asian (EAS) AF: 0.0317 AC: 164 AN: 5170

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

European-Finnish (FIN) AF: 0.135 AC: 1427 AN: 10580

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7242 AN: 67998

Other (OTH) AF: 0.158 AC: 334 AN: 2112

Alfa AF: 0.123 Hom.: 1860

Bravo AF: 0.177

Asia WGS AF: 0.166 AC: 577 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0040
DANN	Benign	0.41
PhyloP100		-3.3
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: rs835576; hg19: chr1-120455586; COSMIC: COSV56710987; COSMIC: COSV56710987;