16-50712018-C-T

Variant summary

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

The NM_001370466.1(NOD2):c.2026C>T(p.Arg676Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00395 in 1,613,156 control chromosomes in the GnomAD database, including 20 homozygotes. 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. R676H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 16 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 4.39

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=0.0068291724).

BP6

Variant 16-50712018-C-T is Benign according to our data. Variant chr16-50712018-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197333.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=2}. Variant chr16-50712018-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00331 (504/152384) while in subpopulation NFE AF= 0.00511 (348/68036). AF 95% confidence interval is 0.00467. There are 4 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd 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.2026C>T	p.Arg676Cys	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.2026C>T	p.Arg676Cys	missense_variant	4/12		NM_001370466.1	P1	Q9HC29-2
NOD2	ENST00000300589.6 linkuse as main transcript	c.2107C>T	p.Arg703Cys	missense_variant	4/12	1			Q9HC29-1
NOD2	ENST00000641284.2 linkuse as main transcript	c.2026C>T	p.Arg676Cys	missense_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2 linkuse as main transcript	c.2026C>T	p.Arg676Cys	missense_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes

AF:

0.00330

AC:

503

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00510

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00321

AC:

798

AN:

248652

Hom.:

AF XY:

0.00317

AC XY:

428

AN XY:

134888

show subpopulations

Gnomad AFR exome

AF:

0.000826

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.00330

Gnomad EAS exome

AF:

0.000764

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00290

Gnomad NFE exome

AF:

0.00549

Gnomad OTH exome

AF:

0.00230

GnomAD4 exome

AF:

0.00402

AC:

5866

AN:

1460772

Hom.:

Cov.:

AF XY:

0.00393

AC XY:

2856

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00318

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00306

Gnomad4 NFE exome

AF:

0.00477

Gnomad4 OTH exome

AF:

0.00323

GnomAD4 genome

AF:

0.00331

AC:

504

AN:

152384

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

223

AN XY:

74522

show subpopulations

Gnomad4 AFR

AF:

0.000793

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00230

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00511

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00369

Hom.:

Bravo

AF:

0.00350

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00698

AC:

ExAC

AF:

0.00327

AC:

397

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00502

EpiControl

AF:

0.00439

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NOD2: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2022	Observed in individuals with inflammatory bowel disease and other auto-inflammatory disorders (Lesage et al., 2002; Yao et al., 2012; Shen et al., 2015; Androletti et al., 2017; Burillo-Sanz et al., 2017; Li et al., 2020); Case control studies suggest this variant may be associated with Crohn's disease (Rivas et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in 0.32% (887/280050 alleles) in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32707200, 22942351, 26164256, 28814775, 28422189, 26070941, 11875755, 21983784, 33394828, 33927005, 35211104, 34975878) -

Autoinflammatory syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 03, 2022

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 24, 2014

- -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Likely 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

Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Blau syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

Cadd

Uncertain

Dann

Uncertain

1.0

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.0068

T;T

MetaSVM

Benign

-0.63

MutationTaster

Benign

0.96

PrimateAI

Benign

0.39

Polyphen

1.0

D;D

Vest4

0.42

MVP

0.91

MPC

0.45

ClinPred

0.037

GERP RS

3.7

Varity_R

0.26

gMVP

0.52

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