rs34684955

chr16-50699832-G-A

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.337G>A(p.Ala113Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,572 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.55

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032271743).
• BP6: Variant 16-50699832-G-A is Benign according to our data. Variant chr16-50699832-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50699832-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00667 (1016/152326) while in subpopulation AFR AF= 0.023 (955/41566). AF 95% confidence interval is 0.0218. There are 8 homozygotes in gnomad4. There are 495 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.337G>A	p.Ala113Thr	missense_variant	2/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.337G>A	p.Ala113Thr	missense_variant	2/12		NM_001370466.1	P1

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1016 AN: 152208 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00174 AC: 436 AN: 250802 Hom.: 1 AF XY: 0.00131 AC XY: 178 AN XY: 135588

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000630 AC: 920 AN: 1461246 Hom.: 9 Cov.: 33 AF XY: 0.000523 AC XY: 380 AN XY: 726902

Gnomad4 AFR exome AF: 0.0232

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00667 AC: 1016 AN: 152326 Hom.: 8 Cov.: 32 AF XY: 0.00665 AC XY: 495 AN XY: 74488

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00337 Hom.: 0

Bravo AF: 0.00805

ESP6500AA AF: 0.0212 AC: 93

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00198 AC: 240

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 24, 2019

- -

Regional enteritis;C5201146:Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 04, 2022

- -

Inflammatory bowel disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 18, 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

Oct 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	17
Dann	Benign	0.96
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.89	N
PrimateAI	Benign	0.31	T
Polyphen		0.37	.;.;B
Vest4		0.16
MVP		0.60
MPC		0.12
ClinPred		0.023	T
GERP RS		4.3
Varity_R		0.10
gMVP		0.11

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: rs34684955; hg19: chr16-50733743; COSMIC: COSV99039077;