chr16-50712049-G-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001370466.1(NOD2):​c.2057G>A​(p.Arg686His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000738 in 1,612,962 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R686C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013140142).
• BP6: Variant 16-50712049-G-A is Benign according to our data. Variant chr16-50712049-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000512 (78/152250) while in subpopulation NFE AF = 0.000764 (52/68044). AF 95% confidence interval is 0.000598. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 78 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.2057G>A	p.Arg686His	missense	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.2138G>A	p.Arg713His	missense	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.2057G>A	p.Arg686His	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>A	p.Arg686His	missense	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.2138G>A	p.Arg713His	missense	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.2057G>A	p.Arg686His	missense	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152250 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000466 AC: 116 AN: 248772 AF XY: 0.000474

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.000571

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000762 AC: 1113 AN: 1460712 Hom.: 1 Cov.: 33 AF XY: 0.000709 AC XY: 515 AN XY: 726714

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.000291 AC: 13 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26124

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.000171 AC: 9 AN: 52488

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

European-Non Finnish (NFE) AF: 0.000895 AC: 995 AN: 1111846

Other (OTH) AF: 0.000398 AC: 24 AN: 60360

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74388

African (AFR) AF: 0.0000482 AC: 2 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000825 Hom.: 0

Bravo AF: 0.000465

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	Blau syndrome (2)
-	-	1	Inflammatory bowel disease 1 (1)
-	1	-	NOD2-related disorder (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.019
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.9	M
PhyloP100		1.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.057
Sift	Benign	0.35	T
Sift4G	Benign	0.18	T
Polyphen		0.10	B
Vest4		0.17
MVP		0.86
MPC		0.12
ClinPred		0.027	T
GERP RS		4.8
PromoterAI		-0.0046	Neutral
Varity_R		0.039
gMVP		0.26
Mutation Taster		=96/4	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: rs104895483; hg19: chr16-50745960;