rs312262795

Variant names:

• chr1-119968194-G-A
• rs312262795
• NM_024408.4:c.1147C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024408.4(NOTCH2):​c.1147C>T​(p.Pro383Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P383A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.1147C>T	p.Pro383Ser	missense_variant	Exon 7 of 34	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.1147C>T	p.Pro383Ser	missense_variant	Exon 7 of 22		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.1147C>T	p.Pro383Ser	missense_variant	Exon 7 of 34	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.1285C>T		non_coding_transcript_exon_variant	Exon 6 of 14	1
NOTCH2	ENST00000640021.1	n.*271C>T		non_coding_transcript_exon_variant	Exon 4 of 12	5		ENSP00000492223.1
NOTCH2	ENST00000640021.1	n.*271C>T		3_prime_UTR_variant	Exon 4 of 12	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.44
MutPred		0.71		Loss of methylation at K386 (P = 0.0657);.;
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.64
gMVP		0.96

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: rs312262795; hg19: chr1-120510817; COSMIC: COSV99864693;