rs7543643

Positions:

Variant summary

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

The NM_024408.4(NOTCH2):c.3234C>T(p.Cys1078=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,614,044 control chromosomes in the GnomAD database, including 1,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.063 ( 978 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 932 hom. )

Consequence

NOTCH2
NM_024408.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0810

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=-0.76).

BP6

Variant 1-119937960-G-A is Benign according to our data. Variant chr1-119937960-G-A is described in ClinVar as [Benign]. Clinvar id is 261702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119937960-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.081 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 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.3234C>T	p.Cys1078=	synonymous_variant	20/34	ENST00000256646.7
NOTCH2	NM_001200001.2 linkuse as main transcript	c.3234C>T	p.Cys1078=	synonymous_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7 linkuse as main transcript	c.3234C>T	p.Cys1078=	synonymous_variant	20/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0626

AC:

9526

AN:

152072

Hom.:

969

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0206

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.0407

GnomAD3 exomes

AF:

0.0186

AC:

4670

AN:

251256

Hom.:

406

AF XY:

0.0144

AC XY:

1960

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.219

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.000707

Gnomad SAS exome

AF:

0.00921

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00797

AC:

11648

AN:

1461854

Hom.:

932

Cov.:

AF XY:

0.00733

AC XY:

5329

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.227

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.0218

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.00839

Gnomad4 FIN exome

AF:

0.000281

Gnomad4 NFE exome

AF:

0.000880

Gnomad4 OTH exome

AF:

0.0176

GnomAD4 genome

AF:

0.0628

AC:

9565

AN:

152190

Hom.:

978

Cov.:

AF XY:

0.0602

AC XY:

4478

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.215

Gnomad4 AMR

AF:

0.0205

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0120

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00129

Gnomad4 OTH

AF:

0.0403

Alfa

AF:

0.0128

Hom.:

269

Bravo

AF:

0.0713

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00237

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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	-	- -

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

-0.76

CADD

Benign

4.4

DANN

Benign

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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