rs104895432

Positions:

chr16-50711232-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_001370466.1(NOD2):c.1240G>A(p.Glu414Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000318 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 3.38

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24522126).

BP6

Variant 16-50711232-G-A is Benign according to our data. Variant chr16-50711232-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97827.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, not_provided=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000341 (52/152344) while in subpopulation AMR AF= 0.000719 (11/15308). AF 95% confidence interval is 0.000402. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.1240G>A	p.Glu414Lys	missense_variant	4/12	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.1240G>A	p.Glu414Lys	missense_variant	4/12		NM_001370466.1	ENSP00000495993	P1	Q9HC29-2
NOD2	ENST00000300589.6 linkuse as main transcript	c.1321G>A	p.Glu441Lys	missense_variant	4/12	1		ENSP00000300589		Q9HC29-1
NOD2	ENST00000641284.2 linkuse as main transcript	c.1240G>A	p.Glu414Lys	missense_variant, NMD_transcript_variant	4/6			ENSP00000493088
NOD2	ENST00000646677.2 linkuse as main transcript	c.1240G>A	p.Glu414Lys	missense_variant, NMD_transcript_variant	4/13			ENSP00000496533

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000308

AC:

AN:

250350

Hom.:

AF XY:

0.000303

AC XY:

AN XY:

135458

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000505

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.000315

AC:

461

AN:

1461654

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

229

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000301

Gnomad4 NFE exome

AF:

0.000364

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000341

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000362

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000488

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000329

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Blau syndrome

Benign:1Other:1

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. -
not provided, no classification provided	literature only	Unité médicale des maladies autoinflammatoires, CHRU Montpellier	-	- -

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

NOD2: BP4 -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

.;T

Eigen

Benign

0.087

Eigen_PC

Benign

-0.023

FATHMM_MKL

Benign

0.58

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.25

T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

1.1

.;L

MutationTaster

Benign

0.97

PrimateAI

Benign

0.44

PROVEAN

Benign

0.090

.;N

REVEL

Uncertain

0.34

Sift

Benign

0.77

.;T

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.38

MVP

0.86

MPC

0.53

ClinPred

0.11

GERP RS

4.3

Varity_R

0.099

gMVP

0.69

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