rs104895489

Positions:

chr16-50712091-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001370466.1(NOD2):c.2099C>T(p.Pro700Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

NOD2
NM_001370466.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 0.756

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17504716).

BP6

Variant 16-50712091-C-T is Benign according to our data. Variant chr16-50712091-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 97845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, not_provided=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1 linkuse as main transcript	c.2099C>T	p.Pro700Leu	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.2099C>T	p.Pro700Leu	missense_variant	4/12		NM_001370466.1	ENSP00000495993	P1	Q9HC29-2
NOD2	ENST00000300589.6 linkuse as main transcript	c.2180C>T	p.Pro727Leu	missense_variant	4/12	1		ENSP00000300589		Q9HC29-1
NOD2	ENST00000641284.2 linkuse as main transcript	c.2099C>T	p.Pro700Leu	missense_variant, NMD_transcript_variant	4/6			ENSP00000493088
NOD2	ENST00000646677.2 linkuse as main transcript	c.2099C>T	p.Pro700Leu	missense_variant, NMD_transcript_variant	4/13			ENSP00000496533

Frequencies

GnomAD3 genomes

AF:

0.0000919

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000598

AC:

AN:

250828

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135696

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461468

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000919

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000368

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 22, 2021	NOD2 NM_022162 exon 4 p.Pro727Leu (c.2180C>T): This variant has been reported in the literature in 1 individual with Crohn's disease, identified in cis with an additional truncating variant (Lappalainen 2008 PMID:17941079). This variant is present in 14/126450 European alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs104895489). This variant is present in ClinVar (Variation ID:97845). This variant amino acid leucine (Leu) is present in >10 species; this suggests that this variant may not impact the protein. Additional computational prediction tools are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Regional enteritis;C5201146:Blau syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

- -

Blau syndrome

Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.099

.;T

Eigen

Benign

0.038

Eigen_PC

Benign

0.012

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.9

.;L

MutationTaster

Benign

0.98

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.4

.;N

REVEL

Uncertain

0.39

Sift

Benign

0.38

.;T

Sift4G

Uncertain

0.013

.;D

Polyphen

0.81

P;D

Vest4

0.14

MVP

0.88

MPC

0.10

ClinPred

0.13

GERP RS

5.5

Varity_R

0.065

gMVP

0.31

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