rs6685892

Variant names:

• chr1-119915381-A-T
• rs6685892
• NM_024408.4:c.7341T>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024408.4(NOTCH2):​c.7341T>A​(p.Gly2447Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,613,934 control chromosomes in the GnomAD database, including 14,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2979 hom., cov: 33)
  • Exomes 𝑓: 0.11 (11217 hom.)
• Consequence: NOTCH2 NM_024408.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.784
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-119915381-A-T is Benign according to our data. Variant chr1-119915381-A-T is described in ClinVar as Benign. ClinVar VariationId is 261705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.784 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

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.7341T>A	p.Gly2447Gly	synonymous	Exon 34 of 34	NP_077719.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.7341T>A	p.Gly2447Gly	synonymous	Exon 34 of 34	ENSP00000256646.2

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25527 AN: 151994 Hom.: 2968 Cov.: 33

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.123 AC: 30822 AN: 251388 AF XY: 0.122

Gnomad AFR exome AF: 0.336

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.0750

Gnomad EAS exome AF: 0.0295

Gnomad FIN exome AF: 0.132

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.115 AC: 167874 AN: 1461822 Hom.: 11217 Cov.: 32 AF XY: 0.116 AC XY: 84411 AN XY: 727224

African (AFR) AF: 0.332 AC: 11122 AN: 33474

American (AMR) AF: 0.0916 AC: 4098 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 1868 AN: 26136

East Asian (EAS) AF: 0.0221 AC: 877 AN: 39700

South Asian (SAS) AF: 0.182 AC: 15735 AN: 86254

European-Finnish (FIN) AF: 0.134 AC: 7133 AN: 53406

Middle Eastern (MID) AF: 0.0857 AC: 494 AN: 5764

European-Non Finnish (NFE) AF: 0.107 AC: 119280 AN: 1111972

Other (OTH) AF: 0.120 AC: 7267 AN: 60392

GnomAD4 genome AF: 0.168 AC: 25559 AN: 152112 Hom.: 2979 Cov.: 33 AF XY: 0.168 AC XY: 12467 AN XY: 74350

African (AFR) AF: 0.326 AC: 13512 AN: 41496

American (AMR) AF: 0.106 AC: 1628 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3470

East Asian (EAS) AF: 0.0314 AC: 162 AN: 5158

South Asian (SAS) AF: 0.189 AC: 909 AN: 4808

European-Finnish (FIN) AF: 0.135 AC: 1425 AN: 10584

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7226 AN: 67988

Other (OTH) AF: 0.156 AC: 329 AN: 2114

Alfa AF: 0.117 Hom.: 406

Bravo AF: 0.170

Asia WGS AF: 0.166 AC: 576 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hajdu-Cheney syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.64
PhyloP100		-0.78
Mutation Taster		=99/1	polymorphism (auto)

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: rs6685892; hg19: chr1-120458004; COSMIC: COSV56683182; COSMIC: COSV56683182;