1-119937285-G-A

Variant names:

• chr1-119937285-G-A
• rs115325955
• NM_024408.4:c.3519C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024408.4(NOTCH2):​c.3519C>T​(p.Cys1173Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000967 in 1,613,110 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (11 hom.)
• Consequence: NOTCH2 NM_024408.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.123
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 1-119937285-G-A is Benign according to our data. Variant chr1-119937285-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 286618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00243 (370/152304) while in subpopulation AFR AF = 0.00606 (252/41560). AF 95% confidence interval is 0.00545. There are 0 homozygotes in GnomAd4. There are 187 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 370 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.3519C>T	p.Cys1173Cys	synonymous	Exon 21 of 34	NP_077719.2
	NOTCH2	NM_001200001.2		c.3519C>T	p.Cys1173Cys	synonymous	Exon 21 of 22	NP_001186930.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOTCH2	ENST00000256646.7	TSL:1 MANE Select	c.3519C>T	p.Cys1173Cys	synonymous	Exon 21 of 34	ENSP00000256646.2	Q04721
	NOTCH2	ENST00000924185.1		c.3519C>T	p.Cys1173Cys	synonymous	Exon 21 of 34	ENSP00000594244.1
	NOTCH2	ENST00000924186.1		c.3246C>T	p.Cys1082Cys	synonymous	Exon 19 of 32	ENSP00000594245.1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 372 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00145 AC: 364 AN: 251312 AF XY: 0.00134

Gnomad AFR exome AF: 0.00726

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000907

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000815 AC: 1190 AN: 1460806 Hom.: 11 Cov.: 32 AF XY: 0.000837 AC XY: 608 AN XY: 726734

African (AFR) AF: 0.00664 AC: 222 AN: 33442

American (AMR) AF: 0.00221 AC: 99 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26134

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

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.0180 AC: 90 AN: 5010

European-Non Finnish (NFE) AF: 0.000516 AC: 574 AN: 1111886

Other (OTH) AF: 0.00114 AC: 69 AN: 60292

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00251 AC XY: 187 AN XY: 74476

African (AFR) AF: 0.00606 AC: 252 AN: 41560

American (AMR) AF: 0.00281 AC: 43 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00271

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00148

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.59
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs115325955; hg19: chr1-120479908;