rs61736932

Variant names:

• chr16-50711744-C-T
• rs61736932
• NM_001370466.1:c.1752C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001370466.1(NOD2):​c.1752C>T​(p.Ala584Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,188 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: NOD2 NM_001370466.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.77
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-50711744-C-T is Benign according to our data. Variant chr16-50711744-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00807 (1230/152358) while in subpopulation NFE AF = 0.0105 (713/68038). AF 95% confidence interval is 0.00984. There are 8 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1230 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.1752C>T	p.Ala584Ala	synonymous	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.1833C>T	p.Ala611Ala	synonymous	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.1752C>T	p.Ala584Ala	synonymous	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.1752C>T	p.Ala584Ala	synonymous	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.1833C>T	p.Ala611Ala	synonymous	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.1752C>T	p.Ala584Ala	synonymous	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.00809 AC: 1231 AN: 152240 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.00967 AC: 2430 AN: 251352 AF XY: 0.00965

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0233

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.0110 AC: 16035 AN: 1461830 Hom.: 104 Cov.: 34 AF XY: 0.0108 AC XY: 7889 AN XY: 727214

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00215 AC: 96 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 827 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00327 AC: 282 AN: 86256

European-Finnish (FIN) AF: 0.0220 AC: 1173 AN: 53366

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0116 AC: 12949 AN: 1112006

Other (OTH) AF: 0.0107 AC: 644 AN: 60394

GnomAD4 genome AF: 0.00807 AC: 1230 AN: 152358 Hom.: 8 Cov.: 33 AF XY: 0.00862 AC XY: 642 AN XY: 74502

African (AFR) AF: 0.00176 AC: 73 AN: 41584

American (AMR) AF: 0.00255 AC: 39 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3472

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

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.0234 AC: 249 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0105 AC: 713 AN: 68038

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.0109 Hom.: 7

Bravo AF: 0.00683

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00931

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.070
DANN	Benign	0.40
PhyloP100		-2.8
PromoterAI		0.0072	Neutral
Mutation Taster		=99/1	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: rs61736932; hg19: chr16-50745655;