rs104895457

Variant names:

• chr16-50725539-G-A
• rs104895457
• NM_001370466.1:c.2852G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001370466.1(NOD2):​c.2852G>A​(p.Gly951Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,614,106 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (2 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 2.08
• Publications: 3 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15878248).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000397 (58/1461782) while in subpopulation MID AF = 0.00451 (26/5768). AF 95% confidence interval is 0.00316. There are 2 homozygotes in GnomAdExome4. There are 32 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 7 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.2852G>A	p.Gly951Glu	missense	Exon 10 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2933G>A	p.Gly978Glu	missense	Exon 10 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2852G>A	p.Gly951Glu	missense	Exon 9 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.2852G>A	p.Gly951Glu	missense	Exon 10 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2933G>A	p.Gly978Glu	missense	Exon 10 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.2852G>A	p.Gly951Glu	missense	Exon 10 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251126 AF XY: 0.0000295

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461782 Hom.: 2 Cov.: 30 AF XY: 0.0000440 AC XY: 32 AN XY: 727200

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111954

Other (OTH) AF: 0.000116 AC: 7 AN: 60392

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Blau syndrome (3)
-	1	-	Inflammatory bowel disease 1 (1)
-	1	-	not provided (1)
-	1	-	Regional enteritis;C5201146:Blau syndrome (1)
-	-	1	Yao syndrome;C5201146:Blau syndrome;CN260071:Inflammatory bowel disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.089
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.34
Sift	Benign	0.081	T
Sift4G	Benign	0.090	T
Polyphen		1.0	D
Vest4		0.76
MutPred		0.54		Gain of disorder (P = 0.0536)
MVP		0.88
MPC		0.39
ClinPred		0.15	T
GERP RS		2.7
Varity_R		0.072
gMVP		0.65
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs104895457; hg19: chr16-50759450; COSMIC: COSV100318974; COSMIC: COSV100318974;