rs3795666

Positions:

chr1-119916301-G-A

Variant summary

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

The NM_024408.4(NOTCH2):c.6421C>T(p.Leu2141Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,614,214 control chromosomes in the GnomAD database, including 1,184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2141L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.025 ( 79 hom., cov: 33)

Exomes 𝑓: 0.026 ( 1105 hom. )

Consequence

NOTCH2
NM_024408.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.06

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=-0.59).

BP6

Variant 1-119916301-G-A is Benign according to our data. Variant chr1-119916301-G-A is described in ClinVar as [Benign]. Clinvar id is 261704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119916301-G-A is described in Lovd as [Benign]. Variant chr1-119916301-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.06 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0969 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.6421C>T	p.Leu2141Leu	synonymous_variant	34/34	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.6421C>T	p.Leu2141Leu	synonymous_variant	34/34	1	NM_024408.4	ENSP00000256646.2		Q04721

Frequencies

GnomAD3 genomes

AF:

0.0247

AC:

3753

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0409

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.0656

Gnomad SAS

AF:

0.104

Gnomad FIN

AF:

0.0310

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0183

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0433

AC:

10890

AN:

251440

Hom.:

438

AF XY:

0.0455

AC XY:

6185

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.0137

Gnomad AMR exome

AF:

0.0827

Gnomad ASJ exome

AF:

0.0253

Gnomad EAS exome

AF:

0.0717

Gnomad SAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.0182

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0261

AC:

38090

AN:

1461880

Hom.:

1105

Cov.:

AF XY:

0.0285

AC XY:

20697

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.0764

Gnomad4 ASJ exome

AF:

0.0271

Gnomad4 EAS exome

AF:

0.0460

Gnomad4 SAS exome

AF:

0.105

Gnomad4 FIN exome

AF:

0.0329

Gnomad4 NFE exome

AF:

0.0169

Gnomad4 OTH exome

AF:

0.0306

GnomAD4 genome

AF:

0.0248

AC:

3775

AN:

152334

Hom.:

Cov.:

AF XY:

0.0272

AC XY:

2028

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.0411

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.0656

Gnomad4 SAS

AF:

0.104

Gnomad4 FIN

AF:

0.0310

Gnomad4 NFE

AF:

0.0183

Gnomad4 OTH

AF:

0.0312

Alfa

AF:

0.0223

Hom.:

Bravo

AF:

0.0240

Asia WGS

AF:

0.115

AC:

399

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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

-0.59

CADD

Benign

1.5

DANN

Benign

0.47

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