16-50710713-C-T

Variant names:

• chr16-50710713-C-T
• rs2066842
• NM_001370466.1:c.721C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370466.1(NOD2):​c.721C>T​(p.Pro241Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 1,613,482 control chromosomes in the GnomAD database, including 49,081 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P241L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.18 (3211 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45870 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.73
• Publications: 173 publications found

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 Gene-Disease associations (from GenCC):

• Blau syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004554957).
• BP6: Variant 16-50710713-C-T is Benign according to our data. Variant chr16-50710713-C-T is described in ClinVar as Benign. ClinVar VariationId is 319435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370466.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.721C>T	p.Pro241Ser	missense	Exon 4 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.802C>T	p.Pro268Ser	missense	Exon 4 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.721C>T	p.Pro241Ser	missense	Exon 3 of 11	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.721C>T	p.Pro241Ser	missense	Exon 4 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.802C>T	p.Pro268Ser	missense	Exon 4 of 12	ENSP00000300589.2
	NOD2	ENST00000527070.5	TSL:1	c.721C>T	p.Pro241Ser	missense	Exon 4 of 4	ENSP00000435149.2

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27121 AN: 152022 Hom.: 3211 Cov.: 32

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.325

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.218

GnomAD2 exomes AF: 0.188 AC: 47064 AN: 250030 AF XY: 0.195

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.123

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.00584

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.239 AC: 349244 AN: 1461342 Hom.: 45870 Cov.: 40 AF XY: 0.238 AC XY: 173061 AN XY: 726924

African (AFR) AF: 0.0471 AC: 1576 AN: 33478

American (AMR) AF: 0.129 AC: 5748 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 6124 AN: 26128

East Asian (EAS) AF: 0.00343 AC: 136 AN: 39662

South Asian (SAS) AF: 0.147 AC: 12659 AN: 86234

European-Finnish (FIN) AF: 0.162 AC: 8655 AN: 53368

Middle Eastern (MID) AF: 0.252 AC: 1455 AN: 5764

European-Non Finnish (NFE) AF: 0.270 AC: 299865 AN: 1111670

Other (OTH) AF: 0.216 AC: 13026 AN: 60378

GnomAD4 genome AF: 0.178 AC: 27119 AN: 152140 Hom.: 3211 Cov.: 32 AF XY: 0.174 AC XY: 12919 AN XY: 74374

African (AFR) AF: 0.0536 AC: 2226 AN: 41524

American (AMR) AF: 0.178 AC: 2721 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 798 AN: 3468

East Asian (EAS) AF: 0.00870 AC: 45 AN: 5172

South Asian (SAS) AF: 0.126 AC: 608 AN: 4824

European-Finnish (FIN) AF: 0.159 AC: 1682 AN: 10584

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18202 AN: 67962

Other (OTH) AF: 0.219 AC: 462 AN: 2112

Alfa AF: 0.237 Hom.: 15163

Bravo AF: 0.173

TwinsUK AF: 0.263 AC: 975

ALSPAC AF: 0.266 AC: 1027

ESP6500AA AF: 0.0580 AC: 255

ESP6500EA AF: 0.269 AC: 2314

ExAC AF: 0.184 AC: 22295

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 32% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported.

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: From periodic fever analysis: Potential risk allele for Crohn's disease and initiation and the progression of carcinogenesis in gastric mucosa.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Regional enteritis;C5201146:Blau syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autoinflammatory syndrome Benign:1

Jan 20, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inflammatory bowel disease 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.0040
DANN	Benign	0.32
DEOGEN2	Benign	0.097	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		-1.7
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.051
Sift	Benign	0.45	T
Sift4G	Benign	0.16	T
Polyphen		0.029	B
Vest4		0.027
MPC		0.095
ClinPred		0.0023	T
GERP RS		-8.3
Varity_R		0.013
gMVP		0.19
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2066842; hg19: chr16-50744624; COSMIC: COSV56049406; COSMIC: COSV56049406;