rs5743271

Positions:

chr16-50710777-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001370466.1(NOD2):c.785A>G(p.Asn262Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0058 in 1,614,044 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0054 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 44 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.18

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003724575).

BP6

Variant 16-50710777-A-G is Benign according to our data. Variant chr16-50710777-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 319440.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=4, Uncertain_significance=1}. Variant chr16-50710777-A-G is described in Lovd as [Likely_benign]. Variant chr16-50710777-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00541 (824/152214) while in subpopulation NFE AF= 0.00747 (508/67984). AF 95% confidence interval is 0.00693. There are 4 homozygotes in gnomad4. There are 352 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.785A>G	p.Asn262Ser	missense_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2 linkuse as main transcript	c.785A>G	p.Asn262Ser	missense_variant	4/12		NM_001370466.1	P1	Q9HC29-2

Frequencies

GnomAD3 genomes

AF:

0.00536

AC:

815

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00596

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00747

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00440

AC:

1104

AN:

250986

Hom.:

AF XY:

0.00428

AC XY:

581

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00443

Gnomad AMR exome

AF:

0.00579

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000883

Gnomad NFE exome

AF:

0.00677

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00584

AC:

8537

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

4153

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00496

Gnomad4 AMR exome

AF:

0.00599

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.000862

Gnomad4 NFE exome

AF:

0.00692

Gnomad4 OTH exome

AF:

0.00485

GnomAD4 genome

AF:

0.00541

AC:

824

AN:

152214

Hom.:

Cov.:

AF XY:

0.00473

AC XY:

352

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00486

Gnomad4 AMR

AF:

0.00595

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000566

Gnomad4 NFE

AF:

0.00747

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00675

Hom.:

Bravo

AF:

0.00584

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00425

AC:

516

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00638

EpiControl

AF:

0.00688

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NOD2: BS2 -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 21, 2022

- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

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

- -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inflammatory bowel disease 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

NOD2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2020

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). -

Blau syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.68

DEOGEN2

Benign

0.29

.;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.75

T;T

MetaRNN

Benign

0.0037

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.9

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.4

.;N

REVEL

Benign

0.22

Sift

Benign

0.057

.;T

Sift4G

Uncertain

0.053

.;T

Polyphen

0.62

P;B

Vest4

0.28

MVP

0.71

MPC

0.13

ClinPred

0.036

GERP RS

4.5

Varity_R

0.076

gMVP

0.51

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