chr1-119963485-G-A

Position:

• chr1-119963485-G-A

Variant summary

Our verdict is Benign. Variant got -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

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=-0.82).
• BP6: Variant 1-119963485-G-A is Benign according to our data. Variant chr1-119963485-G-A is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.1915+89C>T		intron_variant		ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.1915+89C>T		intron_variant			NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.1915+89C>T		intron_variant		1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.2053+89C>T		intron_variant		1
NOTCH2	ENST00000640021.1	n.*1039+89C>T		intron_variant		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

Gnomad4 AFR exome AF: 0.336

Gnomad4 AMR exome AF: 0.0915

Gnomad4 ASJ exome AF: 0.0712

Gnomad4 EAS exome AF: 0.0216

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.120

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

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0833

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.156

Alfa AF: 0.153 Hom.: 515

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

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	-0.82
CADD	Benign	1.2
DANN	Benign	0.62

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: rs2934381; hg19: chr1-120506108; COSMIC: COSV56687347;