rs147223770

chr1-119935502-A-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PP2 PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024408.4(NOTCH2):c.3625T>G(p.Phe1209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,614,210 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (21 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH2
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.026755065).
• BP6: Variant 1-119935502-A-C is Benign according to our data. Variant chr1-119935502-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 134967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119935502-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00253 (386/152324) while in subpopulation NFE AF= 0.00325 (221/68024). AF 95% confidence interval is 0.0029. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 386 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.3625T>G	p.Phe1209Val	missense_variant	22/34	ENST00000256646.7
NOTCH2	NM_001200001.2	c.3625T>G	p.Phe1209Val	missense_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.3625T>G	p.Phe1209Val	missense_variant	22/34	1	NM_024408.4	P1
NOTCH2	ENST00000478864.1	n.285T>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00254 AC: 386 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00762

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00325 AC: 817 AN: 251444 Hom.: 6 AF XY: 0.00338 AC XY: 460 AN XY: 135894

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00316 AC: 4623 AN: 1461886 Hom.: 21 Cov.: 33 AF XY: 0.00324 AC XY: 2355 AN XY: 727242

Gnomad4 AFR exome AF: 0.000896

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00797

Gnomad4 NFE exome AF: 0.00310

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00253 AC: 386 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74476

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00762

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00297 Hom.: 1

Bravo AF: 0.00209

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00332 AC: 403

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 2021	This variant is associated with the following publications: (PMID: 26485759, 24366360, 32467344, 29642553, 29868112, 25587027, 22662265, 30653986, 26094658, 26553438, 24728327) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	NOTCH2: BS2 -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -

Hajdu-Cheney syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.027	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.85
Sift	Benign	0.063	T
Sift4G	Uncertain	0.041	D
Polyphen		0.94	P
Vest4		0.67
MVP		0.90
MPC		1.7
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.29
gMVP		0.76

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

Other links and lift over

dbSNP: rs147223770; hg19: chr1-120478125; COSMIC: COSV56685441;