chr16-50722629-G-T

Position:

chr16-50722629-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6

The NM_001370466.1(NOD2):c.2641G>T(p.Gly881Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000117 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G881R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 4.50

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-50722629-G-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.116695255).

BP6

Variant 16-50722629-G-T is Benign according to our data. Variant chr16-50722629-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 808041.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=5}. Variant chr16-50722629-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.2641G>T	p.Gly881Cys	missense_variant	8/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.2641G>T	p.Gly881Cys	missense_variant	8/12		NM_001370466.1	ENSP00000495993	P1	Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000223

AC:

AN:

251458

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000118

AC:

173

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000105

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 22, 2022	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 16, 2021	The NOD2 c.2722G>T; p.Gly908Cys variant (rs2066845) has not been reported in individuals with Blau syndrome but has been reported in an individual with orofacial granulomatosis (Mentzer 2016). This variant is reported in ClinVar (Variation ID: 808041). This variant is found in the Ashkenazi Jewish population with an allele frequency of 0.37% (38/10370 alleles) in the Genome Aggregation Database. The glycine at codon 908 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.385). However, given the lack of clinical and functional data, the significance of the p.Gly908Cys variant is uncertain at this time. References: Mentzer A et al. Genetic Association Analysis Reveals Differences in the Contribution of NOD2 Variants to the Clinical Phenotypes of Orofacial Granulomatosis. Inflamm Bowel Dis. 2016 Jul;22(7):1552-8. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2018	- -

Blau syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 09, 2022	This NOD2 variant (rs2066845) has been identified in a large population dataset and the minor allele frequency is neither low enough to consider the variant rare (<0.1%) nor high enough to consider it a population polymorphism (>1%) within the Ashkenazi Jewish subpopulation (gnomAD: 38/10370 alleles; 0.37%; no homozgotes). This patient's ethnicity is reported to be Ashkenazi Jewish. This variant has been reported in ClinVar. While this variant has not been reported in individuals with Blau syndrome, it has been reported in an individual with orofacial granulomatosis. Three bioinformatic tools queried predict that this substitution would be damaging, and the glycine residue at this position is conserved across most mammalian species assessed. Bioinformatic analysis predicts that this variant would not affect normal exon 8 splicing, although this has not been confirmed experimentally to our knowledge. A NOD2 polymorphism affecting the same amino acid residue (p.Gly881Arg) is associated with susceptibility to Crohn disease and Yao syndrome. Due to insufficient evidence that this variant is deleterious, we consider the clinical significance of c.2641G>T to be uncertain at this time. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Inflammatory bowel disease 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

.;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.033

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

1.8

.;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-7.1

.;D

REVEL

Uncertain

0.39

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0050

.;D

Polyphen

1.0

D;D

Vest4

0.74

MutPred

0.54

.;Loss of disorder (P = 0.0592);

MVP

0.83

MPC

0.52

ClinPred

0.33

GERP RS

5.9

Varity_R

0.81

gMVP

0.59

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

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