rs34684955

Variant names:

• chr16-50699832-G-A
• rs34684955
• NM_001370466.1:c.337G>A
• NOD2 p.Ala113Thr

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.337G>A​(p.Ala113Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,613,572 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (9 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.55
• Publications: 8 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: G2P, Genomics England PanelApp, Orphanet, Illumina, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=0.0032271743).
• BP6: Variant 16-50699832-G-A is Benign according to our data. Variant chr16-50699832-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00667 (1016/152326) while in subpopulation AFR AF = 0.023 (955/41566). AF 95% confidence interval is 0.0218. There are 8 homozygotes in GnomAd4. There are 495 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1016 Unknown,AD 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.337G>A	p.Ala113Thr	missense	Exon 2 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.418G>A	p.Ala140Thr	missense	Exon 2 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.337G>A	p.Ala113Thr	missense	Exon 1 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.337G>A	p.Ala113Thr	missense	Exon 2 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.418G>A	p.Ala140Thr	missense	Exon 2 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.337G>A	p.Ala113Thr	missense	Exon 2 of 4	ENSP00000435149.2	E9PLF7

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1016 AN: 152208 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00174 AC: 436 AN: 250802 AF XY: 0.00131

Gnomad AFR exome AF: 0.0237

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000630 AC: 920 AN: 1461246 Hom.: 9 Cov.: 33 AF XY: 0.000523 AC XY: 380 AN XY: 726902

African (AFR) AF: 0.0232 AC: 776 AN: 33478

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52880

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111926

Other (OTH) AF: 0.00134 AC: 81 AN: 60390

GnomAD4 genome AF: 0.00667 AC: 1016 AN: 152326 Hom.: 8 Cov.: 32 AF XY: 0.00665 AC XY: 495 AN XY: 74488

African (AFR) AF: 0.0230 AC: 955 AN: 41566

American (AMR) AF: 0.00327 AC: 50 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00353 Hom.: 0

Bravo AF: 0.00805

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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 (1)
-	-	1	Inflammatory bowel disease 1 (1)
-	-	1	not specified (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.6
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.038
Sift	Benign	0.29	T
Sift4G	Benign	0.17	T
Varity_R		0.10
gMVP		0.11
Mutation Taster		=94/6	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs34684955;

hg19: chr16-50733743;

COSMIC: COSV99039077;