rs368529597

Positions:

• chr1-119950690-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024408.4(NOTCH2):​c.2479+34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,342,260 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (9 hom.)
• Consequence: NOTCH2 NM_024408.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.0500

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034797192).
• BP6: Variant 1-119950690-C-T is Benign according to our data. Variant chr1-119950690-C-T is described in ClinVar as [Benign]. Clinvar id is 133370.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 = 0.000617 (94/152274) while in subpopulation SAS AF= 0.00456 (22/4826). AF 95% confidence interval is 0.00309. There are 1 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 94 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOTCH2	NM_024408.4	c.2479+34G>A		intron_variant		ENST00000256646.7	NP_077719.2
NOTCH2	NM_001200001.2	c.2479+34G>A		intron_variant			NP_001186930.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOTCH2	ENST00000256646.7	c.2479+34G>A		intron_variant		1	NM_024408.4	ENSP00000256646.2
NOTCH2	ENST00000479412.2	n.2651G>A		non_coding_transcript_exon_variant	14/14	1
NOTCH2	ENST00000640021.1	n.*1637G>A		non_coding_transcript_exon_variant	12/12	5		ENSP00000492223.1
NOTCH2	ENST00000640021.1	n.*1637G>A		3_prime_UTR_variant	12/12	5		ENSP00000492223.1

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 94 AN: 152156 Hom.: 1 Cov.: 32

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: 0.00455

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00139 AC: 349 AN: 251202 Hom.: 2 AF XY: 0.00175 AC XY: 238 AN XY: 135748

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 SAS exome AF: 0.00457

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000511

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000857 AC: 1020 AN: 1189986 Hom.: 9 Cov.: 16 AF XY: 0.00104 AC XY: 632 AN XY: 605426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000383

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0000781

Gnomad4 SAS exome AF: 0.00501

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.000617 AC: 94 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74456

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00209 Hom.: 0

Bravo AF: 0.000518

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.2
DANN	Benign	0.71
DEOGEN2	Benign	0.0077	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.98	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.089
MVP		0.19
ClinPred		0.027	T
GERP RS		-3.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs368529597; hg19: chr1-120493313; COSMIC: COSV56685101;