rs3795666

Positions:

• chr1-119916301-G-A

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.6421C>T​(p.Leu2141=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,614,214 control chromosomes in the GnomAD database, including 1,184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (79 hom., cov: 33)
  • Exomes 𝑓: 0.026 (1105 hom.)
• Consequence: NOTCH2 NM_024408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.06

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=-0.59).
• BP6: Variant 1-119916301-G-A is Benign according to our data. Variant chr1-119916301-G-A is described in ClinVar as [Benign]. Clinvar id is 261704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119916301-G-A is described in Lovd as [Benign]. Variant chr1-119916301-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.6421C>T	p.Leu2141=	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.6421C>T	p.Leu2141=	synonymous_variant	34/34	1	NM_024408.4	ENSP00000256646	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3753 AN: 152216 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0656

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0310

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.0433 AC: 10890 AN: 251440 Hom.: 438 AF XY: 0.0455 AC XY: 6185 AN XY: 135882

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.0827

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.0717

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0335

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0261 AC: 38090 AN: 1461880 Hom.: 1105 Cov.: 32 AF XY: 0.0285 AC XY: 20697 AN XY: 727244

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.0764

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.0460

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0329

Gnomad4 NFE exome AF: 0.0169

Gnomad4 OTH exome AF: 0.0306

GnomAD4 genome AF: 0.0248 AC: 3775 AN: 152334 Hom.: 79 Cov.: 33 AF XY: 0.0272 AC XY: 2028 AN XY: 74496

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0411

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0656

Gnomad4 SAS AF: 0.104

Gnomad4 FIN AF: 0.0310

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0223 Hom.: 25

Bravo AF: 0.0240

Asia WGS AF: 0.115 AC: 399 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-0.59
CADD	Benign	1.5
DANN	Benign	0.47

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: rs3795666; hg19: chr1-120458924; COSMIC: COSV56686234;