rs61736932

chr16-50711744-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001370466.1(NOD2):c.1752C>T(p.Ala584=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,188 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: NOD2 NM_001370466.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.77

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-50711744-C-T is Benign according to our data. Variant chr16-50711744-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 319451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50711744-C-T is described in Lovd as [Benign]. Variant chr16-50711744-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00807 (1230/152358) while in subpopulation NFE AF= 0.0105 (713/68038). AF 95% confidence interval is 0.00984. There are 8 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.1752C>T	p.Ala584=	synonymous_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.1752C>T	p.Ala584=	synonymous_variant	4/12		NM_001370466.1	P1
NOD2	ENST00000300589.6	c.1833C>T	p.Ala611=	synonymous_variant	4/12	1
NOD2	ENST00000641284.2	c.1752C>T	p.Ala584=	synonymous_variant, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2	c.1752C>T	p.Ala584=	synonymous_variant, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1231 AN: 152240 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00967 AC: 2430 AN: 251352 Hom.: 15 AF XY: 0.00965 AC XY: 1311 AN XY: 135864

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0110 AC: 16035 AN: 1461830 Hom.: 104 Cov.: 34 AF XY: 0.0108 AC XY: 7889 AN XY: 727214

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.0316

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.00807 AC: 1230 AN: 152358 Hom.: 8 Cov.: 33 AF XY: 0.00862 AC XY: 642 AN XY: 74502

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0234

Gnomad4 NFE AF: 0.0105

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.00683

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NOD2: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Regional enteritis;C5201146:Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 05, 2022

- -

Inflammatory bowel disease 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.070
Dann	Benign	0.40

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

Other links and lift over

dbSNP: rs61736932; hg19: chr16-50745655;