rs104895489

Variant names:

• chr16-50712091-C-A
• rs104895489
• NM_001370466.1:c.2099C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-50712091-C-A
• chr16-50712091-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370466.1(NOD2):​c.2099C>A​(p.Pro700Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P700L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.756
• Publications: 0 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: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10962951).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.2099C>A	p.Pro700Gln	missense	Exon 4 of 12	NP_001357395.1
	NOD2	NM_022162.3		c.2180C>A	p.Pro727Gln	missense	Exon 4 of 12	NP_071445.1
	NOD2	NM_001293557.2		c.2099C>A	p.Pro700Gln	missense	Exon 3 of 11	NP_001280486.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.2099C>A	p.Pro700Gln	missense	Exon 4 of 12	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.2180C>A	p.Pro727Gln	missense	Exon 4 of 12	ENSP00000300589.2
	NOD2	ENST00000641284.2		n.2099C>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000493088.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461468 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727046

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.00063	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.057
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.76
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.20
Sift	Benign	0.54	T
Sift4G	Uncertain	0.048	D
Polyphen		0.26	B
Vest4		0.26
MutPred		0.29		Gain of MoRF binding (P = 0.0892)
MVP		0.91
MPC		0.099
ClinPred		0.44	T
GERP RS		5.5
PromoterAI		0.024	Neutral
Varity_R		0.072
gMVP		0.29

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: rs104895489; hg19: chr16-50746002;