rs141935585

Variant names:

• chr1-119967490-G-T
• rs141935585
• NM_024408.4:c.1396C>A

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.1396C>A​(p.Gln466Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000743 in 1,614,102 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q466R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (10 hom.)
• Consequence: NOTCH2 NM_024408.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 5.47
• Publications: 14 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=0.015744537).
• BP6: Variant 1-119967490-G-T is Benign according to our data. Variant chr1-119967490-G-T is described in ClinVar as Benign. ClinVar VariationId is 134968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000611 (93/152302) while in subpopulation SAS AF = 0.00456 (22/4822). AF 95% confidence interval is 0.00309. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 93 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.1396C>A	p.Gln466Lys	missense	Exon 8 of 34	NP_077719.2
	NOTCH2	NM_001200001.2		c.1396C>A	p.Gln466Lys	missense	Exon 8 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.1396C>A	p.Gln466Lys	missense	Exon 8 of 34	ENSP00000256646.2	Q04721
	NOTCH2	ENST00000479412.2	TSL:1	n.1534C>A		non_coding_transcript_exon	Exon 7 of 14
	NOTCH2	ENST00000924185.1		c.1396C>A	p.Gln466Lys	missense	Exon 8 of 34	ENSP00000594244.1

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152184 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00139 AC: 348 AN: 251010 AF XY: 0.00175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000503

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000757 AC: 1106 AN: 1461800 Hom.: 10 Cov.: 32 AF XY: 0.000931 AC XY: 677 AN XY: 727212

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000380 AC: 17 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 310 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39688

South Asian (SAS) AF: 0.00508 AC: 438 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000203 AC: 226 AN: 1111952

Other (OTH) AF: 0.00159 AC: 96 AN: 60390

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152302 Hom.: 1 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74474

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000876 Hom.: 0

Bravo AF: 0.000514

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.49
Sift	Benign	0.050	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.28
MVP		0.79
MPC		0.72
ClinPred		0.028	T
GERP RS		4.8
Varity_R		0.41
gMVP		0.83
Mutation Taster		=89/11	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: rs141935585; hg19: chr1-120510113;