chr16-50712085-C-G

Position:

• chr16-50712085-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001370466.1(NOD2):​c.2093C>G​(p.Ala698Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,806 control chromosomes in the GnomAD database, including 103 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (55 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.55

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024296641).
• BP6: Variant 16-50712085-C-G is Benign according to our data. Variant chr16-50712085-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 319461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50712085-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0124 (1883/152392) while in subpopulation AFR AF= 0.0433 (1800/41598). AF 95% confidence interval is 0.0416. There are 48 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 48 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2093C>G	p.Ala698Gly	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	c.2093C>G	p.Ala698Gly	missense_variant	4/12		NM_001370466.1	ENSP00000495993.1
NOD2	ENST00000300589.6	c.2174C>G	p.Ala725Gly	missense_variant	4/12	1		ENSP00000300589.2
NOD2	ENST00000641284.2	n.2093C>G		non_coding_transcript_exon_variant	4/6			ENSP00000493088.1
NOD2	ENST00000646677.2	n.2093C>G		non_coding_transcript_exon_variant	4/13			ENSP00000496533.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1881 AN: 152274 Hom.: 48 Cov.: 33

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00325 AC: 814 AN: 250736 Hom.: 18 AF XY: 0.00239 AC XY: 324 AN XY: 135666

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00143 AC: 2089 AN: 1461414 Hom.: 55 Cov.: 33 AF XY: 0.00123 AC XY: 895 AN XY: 727012

Gnomad4 AFR exome AF: 0.0507

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.00280

GnomAD4 genome AF: 0.0124 AC: 1883 AN: 152392 Hom.: 48 Cov.: 33 AF XY: 0.0123 AC XY: 919 AN XY: 74526

Gnomad4 AFR AF: 0.0433

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00371 Hom.: 3

Bravo AF: 0.0138

ESP6500AA AF: 0.0380 AC: 167

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00402 AC: 488

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	NOD2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Regional enteritis;C5201146:Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 29, 2021

- -

Inflammatory bowel disease 1 Benign:1

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Blau syndrome Benign:1

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). 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. -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Benign	0.18	.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	.;L
MutationTaster	Benign	0.77	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.087
Sift	Benign	0.15	.;T
Sift4G	Benign	0.26	.;T
Polyphen		0.010	B;B
Vest4		0.17
MVP		0.80
MPC		0.11
ClinPred		0.0082	T
GERP RS		3.8
Varity_R		0.077
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs5743278; hg19: chr16-50745996;