16-50716931-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001370466.1(NOD2):c.2506A>G(p.Met836Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,244 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 11 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.0410

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

Blau syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
inflammatory bowel disease 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060967505).

BP6

Variant 16-50716931-A-G is Benign according to our data. Variant chr16-50716931-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00084 (128/152356) while in subpopulation NFE AF = 0.000838 (57/68024). AF 95% confidence interval is 0.000664. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 128 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1 link	c.2506A>G	p.Met836Val	missense_variant	Exon 6 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2 link	c.2506A>G	p.Met836Val	missense_variant	Exon 6 of 12		NM_001370466.1	ENSP00000495993.1		Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00132

AC:

333

AN:

251496

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00115

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00128

AC:

1875

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

936

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000604

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

391

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00121

AC:

1348

AN:

1112006

Other (OTH)

AF:

0.00157

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

114

228

341

455

569

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000840

AC:

128

AN:

152356

Hom.:

Cov.:

AF XY:

0.000846

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41590

American (AMR)

AF:

0.000196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000838

AC:

AN:

68024

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00144

Hom.:

Bravo

AF:

0.000854

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00120

AC:

146

EpiCase

AF:

0.000872

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOD2: BP4, BS1 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Blau syndrome

Benign:1Other:1

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autoinflammatory syndrome

Benign:1

Mar 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inflammatory bowel disease 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NOD2-related disorder

Benign:1

Jun 11, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.4

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.080

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.0061

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.45

.;N

PhyloP100

-0.041

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.070

.;N

REVEL

Benign

0.057

Sift

Benign

1.0

.;T

Sift4G

Benign

0.33

.;T

Polyphen

0.0

.;B

Vest4

0.31

MVP

0.51

MPC

0.096

ClinPred

0.0048

GERP RS

-9.8

Varity_R

0.020

gMVP

0.37

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over