rs112650847

Variant names:

• chr1-119997088-G-T
• rs112650847
• NM_024408.4:c.660C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-119997088-G-T
• chr1-119997088-G-A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_024408.4(NOTCH2):​c.660C>A​(p.Ser220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.120
• Publications: 6 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Alagille syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, ClinGen
• Alagille syndrome due to a NOTCH2 point mutation

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15923414).
• BP6: Variant 1-119997088-G-T is Benign according to our data. Variant chr1-119997088-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.660C>A	p.Ser220Arg	missense	Exon 4 of 34	NP_077719.2
	NOTCH2	NM_001200001.2		c.660C>A	p.Ser220Arg	missense	Exon 4 of 22	NP_001186930.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.660C>A	p.Ser220Arg	missense	Exon 4 of 34	ENSP00000256646.2	Q04721
	NOTCH2	ENST00000479412.2	TSL:1	n.798C>A		non_coding_transcript_exon	Exon 3 of 14
	NOTCH2	ENST00000924185.1		c.660C>A	p.Ser220Arg	missense	Exon 4 of 34	ENSP00000594244.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000245 AC: 6 AN: 245038 AF XY: 0.0000151

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111824

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 30

Alfa AF: 0.0178 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000906 AC: 11

ClinVar

ClinVar submissions

Significance: Likely 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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.2
DANN	Benign	0.65
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.81	L
PhyloP100		-0.12
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.36	T
Sift4G	Benign	0.38	T
Polyphen		0.97	D
Vest4		0.54
MutPred		0.38		Loss of disorder (P = 0.1501)
MVP		0.80
MPC		1.1
ClinPred		0.043	T
GERP RS		-1.1
Varity_R		0.042
gMVP		0.41
Mutation Taster		=62/38	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: rs112650847; hg19: chr1-120539711; COSMIC: COSV56680697;