Variant 1-119925802-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_024408.4(NOTCH2):c.4014C>T(p.Ser1338=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00837 in 1,614,006 control chromosomes in the GnomAD database, including 699 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 70 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 629 hom. )

Consequence

NOTCH2
NM_024408.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.92

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-119925802-G-A is Benign according to our data. Variant chr1-119925802-G-A is described in ClinVar as [Benign]. Clinvar id is 261703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.92 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4 linkuse as main transcript	c.4014C>T	p.Ser1338=	synonymous_variant	25/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7 linkuse as main transcript	c.4014C>T	p.Ser1338=	synonymous_variant	25/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1762

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0148

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.153

Gnomad SAS

AF:

0.00828

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00256

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0177

AC:

4374

AN:

247344

Hom.:

220

AF XY:

0.0158

AC XY:

2119

AN XY:

134366

show subpopulations

Gnomad AFR exome

AF:

0.0121

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.00290

Gnomad EAS exome

AF:

0.159

Gnomad SAS exome

AF:

0.00350

Gnomad FIN exome

AF:

0.00462

Gnomad NFE exome

AF:

0.00265

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00804

AC:

11745

AN:

1461720

Hom.:

629

Cov.:

AF XY:

0.00782

AC XY:

5683

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.0124

Gnomad4 AMR exome

AF:

0.0183

Gnomad4 ASJ exome

AF:

0.00283

Gnomad4 EAS exome

AF:

0.174

Gnomad4 SAS exome

AF:

0.00427

Gnomad4 FIN exome

AF:

0.00504

Gnomad4 NFE exome

AF:

0.00197

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.0116

AC:

1762

AN:

152286

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

946

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0105

Gnomad4 AMR

AF:

0.0148

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.153

Gnomad4 SAS

AF:

0.00850

Gnomad4 FIN

AF:

0.00480

Gnomad4 NFE

AF:

0.00256

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00445

Hom.:

Bravo

AF:

0.0131

Asia WGS

AF:

0.0610

AC:

211

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Hajdu-Cheney syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.71

DANN

Benign

0.35

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over