1-119948995-C-G

Variant names:

• chr1-119948995-C-G
• rs74117573
• NM_024408.4:c.2599+12G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024408.4(NOTCH2):​c.2599+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00303 in 1,614,158 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (56 hom.)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.178
• Publications: 2 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=-0.73).
• BP6: Variant 1-119948995-C-G is Benign according to our data. Variant chr1-119948995-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1895/152284) while in subpopulation AFR AF = 0.0416 (1729/41552). AF 95% confidence interval is 0.04. There are 37 homozygotes in GnomAd4. There are 895 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1895 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	NM_024408.4	MANE Select	c.2599+12G>C		intron	N/A	NP_077719.2
	NOTCH2	NM_001200001.2		c.2599+12G>C		intron	N/A	NP_001186930.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.2599+12G>C		intron	N/A	ENSP00000256646.2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1886 AN: 152166 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00456 AC: 1146 AN: 251432 AF XY: 0.00394

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00218

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00204 AC: 2989 AN: 1461874 Hom.: 56 Cov.: 32 AF XY: 0.00210 AC XY: 1524 AN XY: 727236

African (AFR) AF: 0.0445 AC: 1490 AN: 33480

American (AMR) AF: 0.00224 AC: 100 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26136

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39700

South Asian (SAS) AF: 0.00788 AC: 680 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5766

European-Non Finnish (NFE) AF: 0.000319 AC: 355 AN: 1112002

Other (OTH) AF: 0.00422 AC: 255 AN: 60394

GnomAD4 genome AF: 0.0124 AC: 1895 AN: 152284 Hom.: 37 Cov.: 32 AF XY: 0.0120 AC XY: 895 AN XY: 74462

African (AFR) AF: 0.0416 AC: 1729 AN: 41552

American (AMR) AF: 0.00379 AC: 58 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68028

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00654 Hom.: 3

Bravo AF: 0.0141

Asia WGS AF: 0.0150 AC: 52 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hajdu-Cheney syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jul 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs74117573; hg19: chr1-120491618;