NM_001370466.1:c.2833G>A

Variant names:

• chr16-50725520-G-A
• rs104895455
• NM_001370466.1:c.2833G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001370466.1(NOD2):​c.2833G>A​(p.Val945Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V945V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 2.03
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High AC in GnomAdExome4 at 11 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.2833G>A	p.Val945Ile	missense	Exon 10 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2914G>A	p.Val972Ile	missense	Exon 10 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2833G>A	p.Val945Ile	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.2833G>A	p.Val945Ile	missense	Exon 10 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2914G>A	p.Val972Ile	missense	Exon 10 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.2833G>A	p.Val945Ile	missense	Exon 10 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251122 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461788 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111930

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Regional enteritis;C5201146:Blau syndrome (1)
-	-	-	Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.79	N
PhyloP100		2.0
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.053
Sift	Benign	0.054	T
Sift4G	Uncertain	0.048	D
Polyphen		0.75	P
Vest4		0.29
MutPred		0.36		Loss of catalytic residue at V972 (P = 0.1424)
MVP		0.80
MPC		0.29
ClinPred		0.46	T
GERP RS		5.0
Varity_R		0.044
gMVP		0.16
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs104895455; hg19: chr16-50759431; COSMIC: COSV56048700; COSMIC: COSV56048700;