1-119915647-G-C

Variant names:

• chr1-119915647-G-C
• rs75831573
• NM_024408.4:c.7075C>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.7075C>G​(p.Pro2359Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00596 in 1,614,064 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2359P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (40 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.34
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006585866).
• BP6: Variant 1-119915647-G-C is Benign according to our data. Variant chr1-119915647-G-C is described in ClinVar as Benign. ClinVar VariationId is 134983.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 = 0.00469 (715/152350) while in subpopulation NFE AF = 0.00675 (459/68034). AF 95% confidence interval is 0.00624. There are 2 homozygotes in GnomAd4. There are 332 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 715 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.7075C>G	p.Pro2359Ala	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.7075C>G	p.Pro2359Ala	missense	Exon 34 of 34	ENSP00000256646.2
	NOTCH2	ENST00000924185.1		c.6937C>G	p.Pro2313Ala	missense	Exon 34 of 34	ENSP00000594244.1
	NOTCH2	ENST00000924186.1		c.6802C>G	p.Pro2268Ala	missense	Exon 32 of 32	ENSP00000594245.1

Frequencies

GnomAD3 genomes AF: 0.00470 AC: 715 AN: 152232 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00675

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00457 AC: 1148 AN: 251234 AF XY: 0.00432

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00609 AC: 8902 AN: 1461714 Hom.: 40 Cov.: 32 AF XY: 0.00574 AC XY: 4174 AN XY: 727144

African (AFR) AF: 0.000717 AC: 24 AN: 33480

American (AMR) AF: 0.00427 AC: 191 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26126

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

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86246

European-Finnish (FIN) AF: 0.00876 AC: 467 AN: 53296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00696 AC: 7742 AN: 1111984

Other (OTH) AF: 0.00651 AC: 393 AN: 60396

GnomAD4 genome AF: 0.00469 AC: 715 AN: 152350 Hom.: 2 Cov.: 33 AF XY: 0.00446 AC XY: 332 AN XY: 74512

African (AFR) AF: 0.00159 AC: 66 AN: 41572

American (AMR) AF: 0.00581 AC: 89 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00800 AC: 85 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00675 AC: 459 AN: 68034

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00571 Hom.: 5

Bravo AF: 0.00472

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00451 AC: 548

EpiCase AF: 0.00611

EpiControl AF: 0.00599

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	15
DANN	Benign	0.59
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.10
MVP		0.63
MPC		0.14
ClinPred		0.0032	T
GERP RS		3.5
Varity_R		0.033
gMVP		0.37
Mutation Taster		=91/9	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: rs75831573; hg19: chr1-120458270;