16-50712049-G-T

Variant names:

• chr16-50712049-G-T
• rs104895483
• NM_001370466.1:c.2057G>T

Variant summary

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

The NM_001370466.1(NOD2):​c.2057G>T​(p.Arg686Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,710 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R686H) 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: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 9 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2057G>T	p.Arg686Leu	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2138G>T	p.Arg713Leu	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2057G>T	p.Arg686Leu	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.2057G>T	p.Arg686Leu	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2138G>T	p.Arg713Leu	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.2057G>T	p.Arg686Leu	missense	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460710 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726712

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111846

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.3
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.37
Sift	Benign	0.11	T
Sift4G	Uncertain	0.013	D
Polyphen		0.87	P
Vest4		0.43
MutPred		0.51		Loss of MoRF binding (P = 0.0214)
MVP		0.90
MPC		0.22
ClinPred		0.96	D
GERP RS		4.8
PromoterAI		-0.019	Neutral
Varity_R		0.11
gMVP		0.44

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: rs104895483; hg19: chr16-50745960;