chr16-50711921-C-A

Variant names:

• chr16-50711921-C-A
• rs104895475
• NM_001370466.1:c.1929C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS3 PM2 PP3_Moderate PP5_Moderate

The NM_001370466.1(NOD2):​c.1929C>A​(p.Asn643Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV001576119: Experimental studies have shown that this missense change affects NOD2 function (PMID:15459013, 20039400, 25093298).". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N643D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.784
• Publications: 15 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: Pathogenic. The variant received 10 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001576119: Experimental studies have shown that this missense change affects NOD2 function (PMID: 15459013, 20039400, 25093298).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 16-50711921-C-A is Pathogenic according to our data. Variant chr16-50711921-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 97842.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1929C>A	p.Asn643Lys	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2010C>A	p.Asn670Lys	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.1929C>A	p.Asn643Lys	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.1929C>A	p.Asn643Lys	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2010C>A	p.Asn670Lys	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.1929C>A	p.Asn643Lys	missense	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

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	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.78
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.83		Gain of ubiquitination at N670 (P = 0.0177)
MVP		0.90
MPC		0.52
ClinPred		0.91	D
GERP RS		2.6
PromoterAI		0.012	Neutral
Varity_R		0.21
gMVP		0.65
Mutation Taster		=83/17	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: rs104895475; hg19: chr16-50745832;