rs35586704

Variant names:

• chr1-119915499-A-T
• rs35586704
• NM_024408.4:c.7223T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-119915499-A-T
• chr1-119915499-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024408.4(NOTCH2):​c.7223T>A​(p.Leu2408His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,614,018 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2408L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:8 O:1
• Conservation: PhyloP100: 3.07
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01960677).
• BP6: Variant 1-119915499-A-T is Benign according to our data. Variant chr1-119915499-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00216 (329/152266) while in subpopulation NFE AF = 0.00337 (229/68010). AF 95% confidence interval is 0.00301. There are 0 homozygotes in GnomAd4. There are 156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 329 AD gene.

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.7223T>A	p.Leu2408His	missense	Exon 34 of 34	NP_077719.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.7223T>A	p.Leu2408His	missense	Exon 34 of 34	ENSP00000256646.2	Q04721
	NOTCH2	ENST00000924185.1		c.7085T>A	p.Leu2362His	missense	Exon 34 of 34	ENSP00000594244.1
	NOTCH2	ENST00000924186.1		c.6950T>A	p.Leu2317His	missense	Exon 32 of 32	ENSP00000594245.1

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00203 AC: 509 AN: 251304 AF XY: 0.00203

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00299 AC: 4365 AN: 1461752 Hom.: 13 Cov.: 32 AF XY: 0.00290 AC XY: 2111 AN XY: 727170

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86254

European-Finnish (FIN) AF: 0.00172 AC: 92 AN: 53362

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00356 AC: 3958 AN: 1111944

Other (OTH) AF: 0.00278 AC: 168 AN: 60392

GnomAD4 genome AF: 0.00216 AC: 329 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00210 AC XY: 156 AN XY: 74462

African (AFR) AF: 0.000890 AC: 37 AN: 41568

American (AMR) AF: 0.00281 AC: 43 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 68010

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00211

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00179 AC: 217

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	1	Hajdu-Cheney syndrome (1)
-	-	1	Hajdu-Cheney syndrome;C1857761:Alagille syndrome due to a NOTCH2 point mutation (1)
-	1	-	Hirschsprung disease, susceptibility to, 1 (1)
-	-	1	NOTCH2-related disorder (1)
-	-	1	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.013	D
MutationAssessor	Benign	1.1	L
PhyloP100		3.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.054	T
Polyphen		1.0	D
Vest4		0.55
MVP		0.95
MPC		0.70
ClinPred		0.016	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.30
Mutation Taster		=79/21	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: rs35586704; hg19: chr1-120458122; COSMIC: COSV104375134;