NM_024408.4:c.2026+1064G>C

Variant names:

• chr1-119958328-C-G
• rs17186372
• NM_024408.4:c.2026+1064G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024408.4(NOTCH2):​c.2026+1064G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 152,246 control chromosomes in the GnomAD database, including 302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.055 (302 hom., cov: 32)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.2026+1064G>C		intron_variant	Intron 12 of 33	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.2026+1064G>C		intron_variant	Intron 12 of 21		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.2026+1064G>C		intron_variant	Intron 12 of 33	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.2164+1064G>C		intron_variant	Intron 11 of 13	1
NOTCH2	ENST00000640021.1	n.*1150+1064G>C		intron_variant	Intron 9 of 11	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8398 AN: 152128 Hom.: 301 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0492

Gnomad ASJ AF: 0.0681

Gnomad EAS AF: 0.0239

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.0530

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.0684

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

GnomAD4 genome AF: 0.0552 AC: 8406 AN: 152246 Hom.: 302 Cov.: 32 AF XY: 0.0571 AC XY: 4252 AN XY: 74426

African (AFR) AF: 0.0456 AC: 1893 AN: 41530

American (AMR) AF: 0.0494 AC: 756 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0681 AC: 236 AN: 3466

East Asian (EAS) AF: 0.0237 AC: 123 AN: 5182

South Asian (SAS) AF: 0.168 AC: 809 AN: 4824

European-Finnish (FIN) AF: 0.0530 AC: 562 AN: 10612

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0560 AC: 3812 AN: 68012

Other (OTH) AF: 0.0676 AC: 143 AN: 2114

Alfa AF: 0.0148 Hom.: 5

Bravo AF: 0.0520

Asia WGS AF: 0.114 AC: 397 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.1
DANN	Benign	0.46
PhyloP100		0.27
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: rs17186372; hg19: chr1-120500951;