1-119922639-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024408.4(NOTCH2):c.4999G>A(p.Val1667Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,614,022 control chromosomes in the GnomAD database, including 8 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1667F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.522

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOTCH2
• BP4: Computational evidence support a benign effect (MetaRNN=0.007403612).
• BP6: Variant 1-119922639-C-T is Benign according to our data. Variant chr1-119922639-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119922639-C-T is described in Lovd as [Likely_benign]. Variant chr1-119922639-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0021 (320/152292) while in subpopulation NFE AF= 0.00329 (224/68038). AF 95% confidence interval is 0.00294. There are 1 homozygotes in gnomad4. There are 144 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 321 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.4999G>A	p.Val1667Ile	missense_variant	27/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.4999G>A	p.Val1667Ile	missense_variant	27/34	1	NM_024408.4	P1
NOTCH2	ENST00000493703.1	n.409G>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00185 AC: 466 AN: 251354 Hom.: 1 AF XY: 0.00193 AC XY: 262 AN XY: 135850

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.00223

Gnomad NFE exome AF: 0.00270

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00303 AC: 4433 AN: 1461730 Hom.: 7 Cov.: 32 AF XY: 0.00301 AC XY: 2189 AN XY: 727172

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.00244

Gnomad4 NFE exome AF: 0.00348

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.00193 AC XY: 144 AN XY: 74472

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.00180

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00184 AC: 223

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	NOTCH2: PP2, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2020	This variant is associated with the following publications: (PMID: 30304577, 28776642) -

not specified Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 13, 2017	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hajdu-Cheney syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Hajdu-Cheney syndrome;C1857761:Alagille syndrome due to a NOTCH2 point mutation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.6
Dann	Benign	0.75
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.088	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.0050
Sift	Benign	0.40	T
Sift4G	Benign	0.45	T
Polyphen		0.0010	B
Vest4		0.025
MVP		0.15
MPC		0.46
ClinPred		0.0024	T
GERP RS		-5.9
Varity_R		0.023
gMVP		0.13

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: rs17024517; hg19: chr1-120465262; COSMIC: COSV56681276;