chr16-50729880-A-G

Position:

chr16-50729880-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001370466.1(NOD2):c.2948A>G(p.Asn983Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,612,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

NOD2 (HGNC:5331): (nucleotide binding oligomerization domain containing 2) This gene is a member of the Nod1/Apaf-1 family and encodes a protein with two caspase recruitment (CARD) domains and six leucine-rich repeats (LRRs). The protein is primarily expressed in the peripheral blood leukocytes. It plays a role in the immune response to intracellular bacterial lipopolysaccharides (LPS) by recognizing the muramyl dipeptide (MDP) derived from them and activating the NFKB protein. Mutations in this gene have been associated with Crohn disease and Blau syndrome. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

NOD2 links:

CYLD-AS1 (HGNC:55352): (CYLD antisense RNA 1)

CYLD-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.2948A>G	p.Asn983Ser	missense_variant	11/12	ENST00000647318.2
CYLD-AS1	NR_184279.1 linkuse as main transcript	n.486T>C		non_coding_transcript_exon_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.2948A>G	p.Asn983Ser	missense_variant	11/12		NM_001370466.1	P1	Q9HC29-2
CYLD-AS1	ENST00000563315.2 linkuse as main transcript	n.1087T>C		non_coding_transcript_exon_variant	4/6	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251386

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460732

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726722

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Regional enteritis;C5201146:Blau syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 02, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NOD2 function (PMID: 15044951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NOD2 protein function. This variant has not been reported in the literature in individuals affected with NOD2-related conditions. This variant is present in population databases (rs367905706, gnomAD 0.006%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1010 of the NOD2 protein (p.Asn1010Ser). -

NOD2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 14, 2023

The NOD2 c.3029A>G variant is predicted to result in the amino acid substitution p.Asn1010Ser. To our knowledge, this variant has not been reported in individuals with NOD2-related condition. Functional studies did not provide clear evidence if the p.Asn1010Ser substitution could lead malfunction of the protein (Tanabe et al. PubMed ID:15044951). This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-50763791-A-G). A different substitution affecting the same amino acid (p.Asn1010Lys) was reported in one family with multiple individuals affected with Crohn’s Disease (Frade-Proud'Hon-Clerc et al. 2019. PubMed ID: 30769939). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.58

MutationAssessor

Pathogenic

2.9

.;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.2

.;D

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.013

.;D

Polyphen

1.0

.;D

Vest4

0.71

MVP

0.89

MPC

0.45

ClinPred

0.99

GERP RS

5.6

Varity_R

0.60

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over