1-119963685-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_024408.4(NOTCH2):​c.1804G>A​(p.Ala602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000482 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00049 ( 0 hom. )

Consequence

NOTCH2
NM_024408.4 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.995
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.043528587).
BP6
Variant 1-119963685-C-T is Benign according to our data. Variant chr1-119963685-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 500000.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr1-119963685-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000368 (56/152154) while in subpopulation NFE AF= 0.000764 (52/68036). AF 95% confidence interval is 0.000598. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NOTCH2NM_024408.4 linkc.1804G>A p.Ala602Thr missense_variant 11/34 ENST00000256646.7 NP_077719.2 Q04721Q6IQ50Q9UFD5
NOTCH2NM_001200001.2 linkc.1804G>A p.Ala602Thr missense_variant 11/22 NP_001186930.1 Q04721Q6IQ50

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NOTCH2ENST00000256646.7 linkc.1804G>A p.Ala602Thr missense_variant 11/341 NM_024408.4 ENSP00000256646.2 Q04721
NOTCH2ENST00000479412.2 linkn.1942G>A non_coding_transcript_exon_variant 10/141
NOTCH2ENST00000640021.1 linkn.*928G>A non_coding_transcript_exon_variant 8/125 ENSP00000492223.1 A0A1W2PQQ5
NOTCH2ENST00000640021.1 linkn.*928G>A 3_prime_UTR_variant 8/125 ENSP00000492223.1 A0A1W2PQQ5

Frequencies

GnomAD3 genomes
AF:
0.000368
AC:
56
AN:
152154
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000764
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000283
AC:
71
AN:
251102
Hom.:
0
AF XY:
0.000251
AC XY:
34
AN XY:
135688
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000564
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000494
AC:
722
AN:
1461812
Hom.:
0
Cov.:
32
AF XY:
0.000476
AC XY:
346
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000615
Gnomad4 OTH exome
AF:
0.000497
GnomAD4 genome
AF:
0.000368
AC:
56
AN:
152154
Hom.:
0
Cov.:
33
AF XY:
0.000336
AC XY:
25
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000764
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000497
Hom.:
0
Bravo
AF:
0.000317
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000412
AC:
50
EpiCase
AF:
0.000763
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:3
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Uncertain significance, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The NOTCH2 p.Ala602Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs140311741), LOVD 3.0 and in ClinVar (classified as a VUS for Hajdu-Cheney syndrome by Invitae and EGL Genetics). The variant was identified in control databases in 85 of 282500 chromosomes at a frequency of 0.000301 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 78 of 128854 chromosomes (freq: 0.000605), Other in 2 of 7220 chromosomes (freq: 0.000277), African in 2 of 24964 chromosomes (freq: 0.00008), Latino in 2 of 35430 chromosomes (freq: 0.000056) and European (Finnish) in 1 of 25124 chromosomes (freq: 0.00004); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ala602 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityJul 28, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 22, 2018- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Hajdu-Cheney syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 30, 2023- -
NOTCH2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMar 04, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.089
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.36
T;T
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.57
T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.044
T;T
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
-0.18
N;.
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.60
N;.
REVEL
Benign
0.072
Sift
Benign
0.39
T;.
Sift4G
Benign
0.43
T;T
Polyphen
0.96
D;B
Vest4
0.11
MVP
0.34
MPC
0.62
ClinPred
0.020
T
GERP RS
3.9
Varity_R
0.038
gMVP
0.49

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.

Other links and lift over

dbSNP: rs140311741; hg19: chr1-120506308; COSMIC: COSV104560197; API