1-119997088-G-T

Position:

• chr1-119997088-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM2 PP2 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. 15/21 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOTCH2. . Gene score misZ 3.5024 (greater than the threshold 3.09). Trascript score misZ 6.0283 (greater than threshold 3.09). GenCC has associacion of gene with Alagille syndrome due to a NOTCH2 point mutation, Alagille syndrome, Acroosteolysis dominant type.
• 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 id is 445811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.660C>A	p.Ser220Arg	missense_variant	4/34	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.660C>A	p.Ser220Arg	missense_variant	4/22		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.660C>A	p.Ser220Arg	missense_variant	4/34	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.798C>A		non_coding_transcript_exon_variant	3/14	1
NOTCH2	ENST00000652302.1	c.660C>A	p.Ser220Arg	missense_variant	4/5			ENSP00000499202.1

Frequencies

GnomAD3 genomes Cov.: 30

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Alfa AF: 0.0178 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 22, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.46	T;T;.
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.81	L;.;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.36	T;.;.
Sift4G	Benign	0.38	T;T;T
Polyphen		0.97	D;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

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: rs112650847; hg19: chr1-120539711; COSMIC: COSV56680697;