rs61752484

chr1-119926524-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.18

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=0.005875975).
• BP6: Variant 1-119926524-T-C is Benign according to our data. Variant chr1-119926524-T-C is described in ClinVar as [Benign]. Clinvar id is 134972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119926524-T-C is described in Lovd as [Benign]. Variant chr1-119926524-T-C is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.3980A>G	p.Asp1327Gly	missense_variant	24/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.3980A>G	p.Asp1327Gly	missense_variant	24/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 928 AN: 152096 Hom.: 6 Cov.: 32

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

GnomAD3 exomes AF: 0.0111 AC: 2633 AN: 238222 Hom.: 60 AF XY: 0.0137 AC XY: 1761 AN XY: 128242

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 SAS exome AF: 0.0517

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.: 31 AF XY: 0.0104 AC XY: 7507 AN XY: 721794

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.00425

Gnomad4 ASJ exome AF: 0.00513

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0522

Gnomad4 FIN exome AF: 0.00268

Gnomad4 NFE exome AF: 0.00678

Gnomad4 OTH exome AF: 0.00897

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152214 Hom.: 6 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74420

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0440

Gnomad4 FIN AF: 0.00274

Gnomad4 NFE AF: 0.00737

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00759 Hom.: 11

Bravo AF: 0.00493

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.0117 AC: 1417

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	This variant is associated with the following publications: (PMID: 31555317, 16773578, 27058611, 23597238, 29221435) -

Hajdu-Cheney syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.36	N
MutationTaster	Benign	0.64	D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.83	N
REVEL	Uncertain	0.40
Sift	Benign	0.41	T
Sift4G	Benign	0.41	T
Polyphen		0.10	B
Vest4		0.23
MPC		0.90
ClinPred		0.011	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs61752484; hg19: chr1-120469147; COSMIC: COSV56685291; COSMIC: COSV56685291;