1-119915381-A-T

Position:

• chr1-119915381-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024408.4(NOTCH2):​c.7341T>A​(p.Gly2447Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,934 control chromosomes in the GnomAD database, including 14,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2979 hom., cov: 33)
  • Exomes 𝑓: 0.11 (11217 hom.)
• Consequence: NOTCH2 NM_024408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.784

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-119915381-A-T is Benign according to our data. Variant chr1-119915381-A-T is described in ClinVar as [Benign]. Clinvar id is 261705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119915381-A-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.784 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.7341T>A	p.Gly2447Gly	synonymous_variant	34/34	ENST00000256646.7	NP_077719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.7341T>A	p.Gly2447Gly	synonymous_variant	34/34	1	NM_024408.4	ENSP00000256646.2

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25527 AN: 151994 Hom.: 2968 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.123 AC: 30822 AN: 251388 Hom.: 2587 AF XY: 0.122 AC XY: 16611 AN XY: 135880

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.0295

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.115 AC: 167874 AN: 1461822 Hom.: 11217 Cov.: 32 AF XY: 0.116 AC XY: 84411 AN XY: 727224

Gnomad4 AFR exome AF: 0.332

Gnomad4 AMR exome AF: 0.0916

Gnomad4 ASJ exome AF: 0.0715

Gnomad4 EAS exome AF: 0.0221

Gnomad4 SAS exome AF: 0.182

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.168 AC: 25559 AN: 152112 Hom.: 2979 Cov.: 33 AF XY: 0.168 AC XY: 12467 AN XY: 74350

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.0836

Gnomad4 EAS AF: 0.0314

Gnomad4 SAS AF: 0.189

Gnomad4 FIN AF: 0.135

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.156

Alfa AF: 0.117 Hom.: 406

Bravo AF: 0.170

Asia WGS AF: 0.166 AC: 576 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Eurofins Ntd Llc (ga)	Mar 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hajdu-Cheney syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.64

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: rs6685892; hg19: chr1-120458004; COSMIC: COSV56683182; COSMIC: COSV56683182;