rs3795666

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

acroosteolysis dominant type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Alagille syndrome due to a NOTCH2 point mutation
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Alagille syndrome
Inheritance: AD Classification: MODERATE Submitted by: Illumina

NOTCH2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 261704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4 link	c.6421C>T	p.Leu2141Leu	synonymous_variant	Exon 34 of 34	ENST00000256646.7	NP_077719.2	Q04721Q6IQ50Q9UFD5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7 link	c.6421C>T	p.Leu2141Leu	synonymous_variant	Exon 34 of 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

GnomAD2 exomes

AF:

0.0433

AC:

10890

AN:

251440

AF XY:

0.0455

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 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

African (AFR)

AF:

0.0128

AC:

427

AN:

33480

American (AMR)

AF:

0.0764

AC:

3418

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

708

AN:

26132

East Asian (EAS)

AF:

0.0460

AC:

1828

AN:

39700

South Asian (SAS)

AF:

0.105

AC:

9029

AN:

86256

European-Finnish (FIN)

AF:

0.0329

AC:

1755

AN:

53420

Middle Eastern (MID)

AF:

0.0465

AC:

268

AN:

5768

European-Non Finnish (NFE)

AF:

0.0169

AC:

18807

AN:

1112004

Other (OTH)

AF:

0.0306

AC:

1850

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

2794

5588

8381

11175

13969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

814

1628

2442

3256

4070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0248

AC:

3775

AN:

152334

Hom.:

Cov.:

AF XY:

0.0272

AC XY:

2028

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0138

AC:

573

AN:

41572

American (AMR)

AF:

0.0411

AC:

629

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3472

East Asian (EAS)

AF:

0.0656

AC:

340

AN:

5184

South Asian (SAS)

AF:

0.104

AC:

504

AN:

4828

European-Finnish (FIN)

AF:

0.0310

AC:

329

AN:

10630

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0183

AC:

1247

AN:

68016

Other (OTH)

AF:

0.0312

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

184

368

551

735

919

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0220

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Hajdu-Cheney syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

1.5

(source)

DANN

Benign

0.47

PhyloP100

2.1

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over