rs60854092

chr1-119922384-T-Achr1-119922384-T-C

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.5065A>T(p.Ile1689Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,078 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.236

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=0.009764969).
• BP6: Variant 1-119922384-T-A is Benign according to our data. Variant chr1-119922384-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 134978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119922384-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00108 (164/152228) while in subpopulation EAS AF= 0.0276 (143/5180). AF 95% confidence interval is 0.0239. There are 2 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 164 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.5065A>T	p.Ile1689Phe	missense_variant	28/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.5065A>T	p.Ile1689Phe	missense_variant	28/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152110 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00204 AC: 512 AN: 251330 Hom.: 10 AF XY: 0.00188 AC XY: 255 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0251

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00112 AC: 1630 AN: 1461850 Hom.: 24 Cov.: 32 AF XY: 0.00109 AC XY: 794 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0354

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00127

Gnomad4 NFE exome AF: 0.0000755

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152228 Hom.: 2 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000986 Hom.: 2

Bravo AF: 0.00124

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00190 AC: 231

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hajdu-Cheney syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

NOTCH2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 21, 2021

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Uncertain	0.97
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.40
Sift	Benign	0.061	T
Sift4G	Uncertain	0.016	D
Polyphen		0.66	P
Vest4		0.57
MVP		0.86
MPC		1.2
ClinPred		0.038	T
GERP RS		2.8
Varity_R		0.083
gMVP		0.59

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: rs60854092; hg19: chr1-120465007; COSMIC: COSV56686315; COSMIC: COSV56686315;