16-50711180-G-T

Variant names:

• chr16-50711180-G-T
• rs77966199
• NM_001370466.1:c.1188G>T

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.1188G>T​(p.Val396Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,614,106 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V396V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: NOD2 NM_001370466.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.74
• Publications: 2 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 (BayesDel_noAF=-0.55).
• BP6: Variant 16-50711180-G-T is Benign according to our data. Variant chr16-50711180-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319443.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 = 0.00246 (374/152336) while in subpopulation AFR AF = 0.00847 (352/41582). AF 95% confidence interval is 0.00774. There are 5 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 374 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.1188G>T	p.Val396Val	synonymous	Exon 4 of 12	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.1269G>T	p.Val423Val	synonymous	Exon 4 of 12	NP_071445.1	Q9HC29-1
	NOD2	NM_001293557.2		c.1188G>T	p.Val396Val	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.1188G>T	p.Val396Val	synonymous	Exon 4 of 12	ENSP00000495993.1	Q9HC29-2
	NOD2	ENST00000300589.6	TSL:1	c.1269G>T	p.Val423Val	synonymous	Exon 4 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000951248.1		c.1188G>T	p.Val396Val	synonymous	Exon 4 of 12	ENSP00000621307.1

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 373 AN: 152218 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

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: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000625 AC: 157 AN: 251132 AF XY: 0.000523

Gnomad AFR exome AF: 0.00826

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000239 AC: 350 AN: 1461770 Hom.: 4 Cov.: 40 AF XY: 0.000195 AC XY: 142 AN XY: 727198

African (AFR) AF: 0.00875 AC: 293 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152336 Hom.: 5 Cov.: 33 AF XY: 0.00240 AC XY: 179 AN XY: 74484

African (AFR) AF: 0.00847 AC: 352 AN: 41582

American (AMR) AF: 0.000980 AC: 15 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

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: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00142 Hom.: 0

Bravo AF: 0.00290

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	NOD2-related disorder (1)
-	-	1	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.3
DANN	Benign	0.41
PhyloP100		1.7
Mutation Taster		=99/1	polymorphism

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: rs77966199; hg19: chr16-50745091;