1-119963373-G-C

Variant names:

• chr1-119963373-G-C
• rs10923929
• NM_024408.4:c.1915+201C>G

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+201C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 152,228 control chromosomes in the GnomAD database, including 40,875 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.67 (40875 hom., cov: 33)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354
• Publications: 6 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=-0.87).
• BP6: Variant 1-119963373-G-C is Benign according to our data. Variant chr1-119963373-G-C is described in ClinVar as Benign. ClinVar VariationId is 1274327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 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.1915+201C>G		intron	N/A	NP_077719.2
	NOTCH2	NM_001200001.2		c.1915+201C>G		intron	N/A	NP_001186930.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.1915+201C>G		intron	N/A	ENSP00000256646.2
	NOTCH2	ENST00000479412.2	TSL:1	n.2053+201C>G		intron	N/A
	NOTCH2	ENST00000640021.1	TSL:5	n.*1039+201C>G		intron	N/A	ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.666 AC: 101269 AN: 152110 Hom.: 40882 Cov.: 33

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.936

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.860

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.835

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.873

Gnomad OTH AF: 0.721

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.665 AC: 101254 AN: 152228 Hom.: 40875 Cov.: 33 AF XY: 0.667 AC XY: 49664 AN XY: 74426

African (AFR) AF: 0.175 AC: 7258 AN: 41512

American (AMR) AF: 0.799 AC: 12224 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.860 AC: 2987 AN: 3472

East Asian (EAS) AF: 0.902 AC: 4677 AN: 5186

South Asian (SAS) AF: 0.687 AC: 3306 AN: 4812

European-Finnish (FIN) AF: 0.835 AC: 8849 AN: 10600

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.873 AC: 59352 AN: 68024

Other (OTH) AF: 0.714 AC: 1509 AN: 2114

Alfa AF: 0.645 Hom.: 2552

Bravo AF: 0.646

Asia WGS AF: 0.671 AC: 2334 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.34
PhyloP100		0.35
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: rs10923929; hg19: chr1-120505996;