rs5743272

Positions:

• chr16-50710966-A-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.974A>G​(p.His325Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000704 in 1,614,170 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H325N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.19

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=0.008668423).
• BP6: Variant 16-50710966-A-G is Benign according to our data. Variant chr16-50710966-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 462694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50710966-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00357 (543/152280) while in subpopulation AFR AF= 0.0124 (514/41562). AF 95% confidence interval is 0.0115. There are 2 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.974A>G	p.His325Arg	missense_variant	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.974A>G	p.His325Arg	missense_variant	4/12		NM_001370466.1	P1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 542 AN: 152162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.00239

GnomAD3 exomes AF: 0.000959 AC: 241 AN: 251434 Hom.: 3 AF XY: 0.000773 AC XY: 105 AN XY: 135898

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000406 AC: 593 AN: 1461890 Hom.: 2 Cov.: 39 AF XY: 0.000355 AC XY: 258 AN XY: 727246

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000863

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00345 AC XY: 257 AN XY: 74456

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.00131

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: 0.00237

Alfa AF: 0.000618 Hom.: 0

Bravo AF: 0.00373

ESP6500AA AF: 0.00955 AC: 42

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00110 AC: 133

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 12, 2020

- -

Regional enteritis;C5201146:Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.98
Eigen	Benign	-0.015
Eigen_PC	Benign	0.0035
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0087	T;T
MetaSVM	Benign	-0.28	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.53	T
Polyphen		0.91	P;P
Vest4		0.47
MVP		0.90
MPC		0.42
ClinPred		0.060	T
GERP RS		4.7
Varity_R		0.43
gMVP		0.80

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: rs5743272; hg19: chr16-50744877;