1-119963373-G-C

Position:

• chr1-119963373-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000256646.7(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 ENST00000256646.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.354

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.1915+201C>G		intron_variant		ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.1915+201C>G		intron_variant			NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.1915+201C>G		intron_variant		1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.2053+201C>G		intron_variant		1
NOTCH2	ENST00000640021.1	n.*1039+201C>G		intron_variant		5		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

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.799

Gnomad4 ASJ AF: 0.860

Gnomad4 EAS AF: 0.902

Gnomad4 SAS AF: 0.687

Gnomad4 FIN AF: 0.835

Gnomad4 NFE AF: 0.873

Gnomad4 OTH AF: 0.714

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs10923929; hg19: chr1-120505996; COSMIC: COSV56681705;