rs34561092

chr1-119925505-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024408.4(NOTCH2):c.4311C>T(p.Gly1437=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,094 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (13 hom.)
• Consequence: NOTCH2 NM_024408.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.787

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=-0.69).
• BP6: Variant 1-119925505-G-A is Benign according to our data. Variant chr1-119925505-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 286546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-119925505-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.787 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00688 (1047/152212) while in subpopulation AFR AF= 0.0232 (965/41510). AF 95% confidence interval is 0.022. There are 4 homozygotes in gnomad4. There are 463 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1044 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOTCH2	NM_024408.4	c.4311C>T	p.Gly1437=	synonymous_variant	25/34	ENST00000256646.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOTCH2	ENST00000256646.7	c.4311C>T	p.Gly1437=	synonymous_variant	25/34	1	NM_024408.4	P1

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152094 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00220 AC: 552 AN: 251246 Hom.: 5 AF XY: 0.00178 AC XY: 242 AN XY: 135828

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.000973 AC: 1422 AN: 1461882 Hom.: 13 Cov.: 33 AF XY: 0.000943 AC XY: 686 AN XY: 727244

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.00268

GnomAD4 genome AF: 0.00688 AC: 1047 AN: 152212 Hom.: 4 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74428

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00413 Hom.: 2

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 03, 2016

- -

Hajdu-Cheney syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2020

- -

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 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	5.1
Dann	Benign	0.55

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: rs34561092; hg19: chr1-120468128; COSMIC: COSV104560075; COSMIC: COSV104560075;