NM_001370466.1:c.785A>G

Variant names:

• chr16-50710777-A-G
• rs5743271
• NM_001370466.1:c.785A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001370466.1(NOD2):​c.785A>G​(p.Asn262Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0058 in 1,614,044 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (44 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 4.18
• Publications: 31 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: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina
• inflammatory bowel disease 1

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003724575).
• BP6: Variant 16-50710777-A-G is Benign according to our data. Variant chr16-50710777-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 319440.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00541 (824/152214) while in subpopulation NFE AF = 0.00747 (508/67984). AF 95% confidence interval is 0.00693. There are 4 homozygotes in GnomAd4. There are 352 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 824 AD,Unknown gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.785A>G	p.Asn262Ser	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.866A>G	p.Asn289Ser	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.785A>G	p.Asn262Ser	missense	Exon 3 of 11	NP_001280486.1	Q9HC29-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.785A>G	p.Asn262Ser	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.866A>G	p.Asn289Ser	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.785A>G	p.Asn262Ser	missense	Exon 4 of 4	ENSP00000435149.2	E9PLF7

Frequencies

GnomAD3 genomes AF: 0.00536 AC: 815 AN: 152096 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00747

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00440 AC: 1104 AN: 250986 AF XY: 0.00428

Gnomad AFR exome AF: 0.00443

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.000883

Gnomad NFE exome AF: 0.00677

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00584 AC: 8537 AN: 1461830 Hom.: 44 Cov.: 40 AF XY: 0.00571 AC XY: 4153 AN XY: 727212

African (AFR) AF: 0.00496 AC: 166 AN: 33478

American (AMR) AF: 0.00599 AC: 268 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86256

European-Finnish (FIN) AF: 0.000862 AC: 46 AN: 53370

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00692 AC: 7697 AN: 1112006

Other (OTH) AF: 0.00485 AC: 293 AN: 60396

GnomAD4 genome AF: 0.00541 AC: 824 AN: 152214 Hom.: 4 Cov.: 33 AF XY: 0.00473 AC XY: 352 AN XY: 74424

African (AFR) AF: 0.00486 AC: 202 AN: 41564

American (AMR) AF: 0.00595 AC: 91 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00747 AC: 508 AN: 67984

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00654 Hom.: 12

Bravo AF: 0.00584

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00425 AC: 516

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00638

EpiControl AF: 0.00688

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Autoinflammatory syndrome (1)
-	-	1	Blau syndrome (1)
-	-	1	Inflammatory bowel disease 1 (1)
-	-	1	NOD2-related disorder (1)
-	-	1	not specified (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.68
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.22
Sift	Benign	0.057	T
Sift4G	Uncertain	0.053	T
Polyphen		0.62	P
Vest4		0.28
MVP		0.71
MPC		0.13
ClinPred		0.036	T
GERP RS		4.5
Varity_R		0.076
gMVP		0.51
Mutation Taster		=94/6	polymorphism

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: rs5743271; hg19: chr16-50744688; COSMIC: COSV100319028; COSMIC: COSV100319028;