1-119925511-C-T

Position:

chr1-119925511-C-T

Variant summary

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

The NM_024408.4(NOTCH2):c.4305G>A(p.Arg1435Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,614,144 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 111 hom., cov: 32)

Exomes 𝑓: 0.012 ( 1063 hom. )

Consequence

NOTCH2
NM_024408.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.569

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 1-119925511-C-T is Benign according to our data. Variant chr1-119925511-C-T is described in ClinVar as [Benign]. Clinvar id is 195907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119925511-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.569 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4 linkuse as main transcript	c.4305G>A	p.Arg1435Arg	synonymous_variant	25/34	ENST00000256646.7	NP_077719.2	Q04721Q6IQ50Q9UFD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7 linkuse as main transcript	c.4305G>A	p.Arg1435Arg	synonymous_variant	25/34	1	NM_024408.4	ENSP00000256646.2		Q04721

Frequencies

GnomAD3 genomes

AF:

0.0156

AC:

2370

AN:

152138

Hom.:

112

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0938

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00112

Gnomad OTH

AF:

0.0192

GnomAD3 exomes

AF:

0.0342

AC:

8604

AN:

251302

Hom.:

584

AF XY:

0.0348

AC XY:

4722

AN XY:

135858

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.00774

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.107

Gnomad FIN exome

AF:

0.0139

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.0240

GnomAD4 exome

AF:

0.0119

AC:

17395

AN:

1461888

Hom.:

1063

Cov.:

AF XY:

0.0142

AC XY:

10338

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.128

Gnomad4 ASJ exome

AF:

0.00826

Gnomad4 EAS exome

AF:

0.00144

Gnomad4 SAS exome

AF:

0.107

Gnomad4 FIN exome

AF:

0.0123

Gnomad4 NFE exome

AF:

0.000613

Gnomad4 OTH exome

AF:

0.0131

GnomAD4 genome

AF:

0.0156

AC:

2370

AN:

152256

Hom.:

111

Cov.:

AF XY:

0.0200

AC XY:

1488

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00270

Gnomad4 AMR

AF:

0.0937

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.0141

Gnomad4 NFE

AF:

0.00112

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.00448

Hom.:

Bravo

AF:

0.0200

Asia WGS

AF:

0.0560

AC:

194

AN:

3478

EpiCase

AF:

0.000927

EpiControl

AF:

0.00124

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -

Hajdu-Cheney syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.1

DANN

Benign

0.57

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

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