rs7533978

Positions:

• chr1-119969680-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_024408.4(NOTCH2):​c.939C>T​(p.Gly313Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,614,062 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (152 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (171 hom.)
• Consequence: NOTCH2 NM_024408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.193

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 1-119969680-G-A is Benign according to our data. Variant chr1-119969680-G-A is described in ClinVar as [Benign]. Clinvar id is 532030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.193 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.939C>T	p.Gly313Gly	synonymous_variant	6/34	ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.939C>T	p.Gly313Gly	synonymous_variant	6/22		NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.939C>T	p.Gly313Gly	synonymous_variant	6/34	1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.1077C>T		non_coding_transcript_exon_variant	5/14	1
NOTCH2	ENST00000640021.1	n.*63C>T		non_coding_transcript_exon_variant	3/12	5		ENSP00000492223.1
NOTCH2	ENST00000640021.1	n.*63C>T		3_prime_UTR_variant	3/12	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3745 AN: 152126 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.0855

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.00635 AC: 1593 AN: 250998 Hom.: 59 AF XY: 0.00435 AC XY: 590 AN XY: 135622

Gnomad AFR exome AF: 0.0867

Gnomad AMR exome AF: 0.00361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000353

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00271 AC: 3965 AN: 1461818 Hom.: 171 Cov.: 33 AF XY: 0.00230 AC XY: 1674 AN XY: 727214

Gnomad4 AFR exome AF: 0.0927

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00594

GnomAD4 genome AF: 0.0246 AC: 3750 AN: 152244 Hom.: 152 Cov.: 32 AF XY: 0.0240 AC XY: 1783 AN XY: 74444

Gnomad4 AFR AF: 0.0854

Gnomad4 AMR AF: 0.00921

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0136 Hom.: 38

Bravo AF: 0.0282

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -

Hajdu-Cheney syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs7533978; hg19: chr1-120512303; COSMIC: COSV104560064;