rs2934381

Variant names:

• chr1-119963485-G-A
• rs2934381
• NM_024408.4:c.1915+89C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024408.4(NOTCH2):​c.1915+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,185,224 control chromosomes in the GnomAD database, including 11,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2970 hom., cov: 32)
  • Exomes 𝑓: 0.12 (8251 hom.)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.572
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-119963485-G-A is Benign according to our data. Variant chr1-119963485-G-A is described in ClinVar as Benign. ClinVar VariationId is 1276223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.1915+89C>T		intron_variant	Intron 11 of 33	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.1915+89C>T		intron_variant	Intron 11 of 21		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.1915+89C>T		intron_variant	Intron 11 of 33	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.2053+89C>T		intron_variant	Intron 10 of 13	1
NOTCH2	ENST00000640021.1	n.*1039+89C>T		intron_variant	Intron 8 of 11	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25472 AN: 152008 Hom.: 2959 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0833

Gnomad EAS AF: 0.0318

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.157

GnomAD4 exome AF: 0.115 AC: 119173 AN: 1033098 Hom.: 8251 AF XY: 0.117 AC XY: 62458 AN XY: 533098

African (AFR) AF: 0.336 AC: 8482 AN: 25272

American (AMR) AF: 0.0915 AC: 4039 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.0712 AC: 1670 AN: 23460

East Asian (EAS) AF: 0.0216 AC: 817 AN: 37786

South Asian (SAS) AF: 0.183 AC: 14111 AN: 77230

European-Finnish (FIN) AF: 0.133 AC: 6817 AN: 51064

Middle Eastern (MID) AF: 0.0860 AC: 420 AN: 4886

European-Non Finnish (NFE) AF: 0.107 AC: 77267 AN: 723024

Other (OTH) AF: 0.120 AC: 5550 AN: 46224

GnomAD4 genome AF: 0.168 AC: 25504 AN: 152126 Hom.: 2970 Cov.: 32 AF XY: 0.167 AC XY: 12447 AN XY: 74376

African (AFR) AF: 0.325 AC: 13495 AN: 41470

American (AMR) AF: 0.106 AC: 1625 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 289 AN: 3468

East Asian (EAS) AF: 0.0315 AC: 163 AN: 5176

South Asian (SAS) AF: 0.189 AC: 910 AN: 4820

European-Finnish (FIN) AF: 0.134 AC: 1421 AN: 10584

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

European-Non Finnish (NFE) AF: 0.106 AC: 7195 AN: 68004

Other (OTH) AF: 0.156 AC: 329 AN: 2110

Alfa AF: 0.157 Hom.: 557

Bravo AF: 0.170

Asia WGS AF: 0.165 AC: 572 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.62
PhyloP100		0.57
Mutation Taster		=99/1	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: rs2934381; hg19: chr1-120506108;