rs835574

Variant names:

• chr1-119920607-C-T
• rs835574
• NM_024408.4:c.5311-210G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024408.4(NOTCH2):​c.5311-210G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 152,068 control chromosomes in the GnomAD database, including 15,645 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.33 (15645 hom., cov: 32)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.391
• Publications: 19 publications found

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]

NOTCH2 Gene-Disease associations (from GenCC):

• acroosteolysis dominant type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Alagille syndrome due to a NOTCH2 point mutation

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Alagille syndrome

  Inheritance: AD Classification: MODERATE Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-119920607-C-T is Benign according to our data. Variant chr1-119920607-C-T is described in ClinVar as Benign. ClinVar VariationId is 1297817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024408.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	NM_024408.4	MANE Select	c.5311-210G>A		intron	N/A	NP_077719.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.5311-210G>A		intron	N/A	ENSP00000256646.2
	NOTCH2	ENST00000924185.1		c.5173-210G>A		intron	N/A	ENSP00000594244.1
	NOTCH2	ENST00000924186.1		c.5038-210G>A		intron	N/A	ENSP00000594245.1

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50663 AN: 151948 Hom.: 15577 Cov.: 32

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.0636

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.277

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.334 AC: 50798 AN: 152068 Hom.: 15645 Cov.: 32 AF XY: 0.332 AC XY: 24686 AN XY: 74364

African (AFR) AF: 0.823 AC: 34108 AN: 41428

American (AMR) AF: 0.200 AC: 3056 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 481 AN: 3468

East Asian (EAS) AF: 0.0984 AC: 509 AN: 5172

South Asian (SAS) AF: 0.312 AC: 1504 AN: 4816

European-Finnish (FIN) AF: 0.165 AC: 1754 AN: 10604

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.128 AC: 8674 AN: 67978

Other (OTH) AF: 0.284 AC: 600 AN: 2110

Alfa AF: 0.192 Hom.: 9804

Bravo AF: 0.354

Asia WGS AF: 0.329 AC: 1142 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.32
DANN	Benign	0.27
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs835574; hg19: chr1-120463230; COSMIC: COSV104375038;