1-119920607-C-T

Position:

• chr1-119920607-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.5311-210G>A		intron_variant		ENST00000256646.7	NP_077719.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.5311-210G>A		intron_variant		1	NM_024408.4	ENSP00000256646	P1

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

Gnomad4 AFR AF: 0.823

Gnomad4 AMR AF: 0.200

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.0984

Gnomad4 SAS AF: 0.312

Gnomad4 FIN AF: 0.165

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.284

Alfa AF: 0.150 Hom.: 3432

Bravo AF: 0.354

Asia WGS AF: 0.329 AC: 1142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.32
DANN	Benign	0.27

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