NM_024408.4:c.3980A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024408.4(NOTCH2):c.3980A>G(p.Asp1327Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00874 in 1,605,286 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0090 ( 209 hom. )

Consequence

NOTCH2
NM_024408.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 2.18

Publications

22 publications found

Variant links:

COSMIC-nc: COSV56685291

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005875975).

BP6

Variant 1-119926524-T-C is Benign according to our data. Variant chr1-119926524-T-C is described in ClinVar as Benign. ClinVar VariationId is 134972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4 link	c.3980A>G	p.Asp1327Gly	missense_variant	Exon 24 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.3980A>G	p.Asp1327Gly	missense_variant	Exon 24 of 34	1	NM_024408.4	ENSP00000256646.2		Q04721

Frequencies

GnomAD3 genomes

AF:

0.00610

AC:

928

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0442

Gnomad FIN

AF:

0.00274

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00738

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.0111

AC:

2633

AN:

238222

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00416

Gnomad ASJ exome

AF:

0.00513

Gnomad EAS exome

AF:

0.000165

Gnomad FIN exome

AF:

0.00234

Gnomad NFE exome

AF:

0.00763

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00903

AC:

13114

AN:

1453072

Hom.:

209

Cov.:

AF XY:

0.0104

AC XY:

7507

AN XY:

721794

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33402

American (AMR)

AF:

0.00425

AC:

187

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.00513

AC:

132

AN:

25730

East Asian (EAS)

AF:

0.000101

AC:

AN:

39684

South Asian (SAS)

AF:

0.0522

AC:

4412

AN:

84564

European-Finnish (FIN)

AF:

0.00268

AC:

142

AN:

52900

Middle Eastern (MID)

AF:

0.0266

AC:

153

AN:

5756

European-Non Finnish (NFE)

AF:

0.00678

AC:

7505

AN:

1106978

Other (OTH)

AF:

0.00897

AC:

539

AN:

60092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

737

1474

2210

2947

3684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.00607

AC:

924

AN:

152214

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

464

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41544

American (AMR)

AF:

0.00399

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0440

AC:

212

AN:

4818

European-Finnish (FIN)

AF:

0.00274

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00737

AC:

501

AN:

68006

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

140

187

234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00749

Hom.:

Bravo

AF:

0.00493

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.0117

AC:

1417

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 14, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31555317, 16773578, 27058611, 23597238, 29221435) -

not specified

Benign:2Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Nov 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.34

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0059

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.36

PhyloP100

2.2

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.83

REVEL

Uncertain

0.40

Sift

Benign

0.41

Sift4G

Benign

0.41

Polyphen

0.10

Vest4

0.23

MPC

0.90

ClinPred

0.011

GERP RS

5.6

Varity_R

0.15

gMVP

0.56

Mutation Taster

=85/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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