ENST00000300589:c.-58T>C

Variant names:

• chr16-50697186-T-C
• rs139485985
• ENST00000300589.6:c.-58T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000300589.6(NOD2):​c.-58T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,448,276 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: NOD2 ENST00000300589.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.52
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-50697186-T-C is Benign according to our data. Variant chr16-50697186-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 319420.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00154 (235/152330) while in subpopulation AFR AF = 0.00548 (228/41582). AF 95% confidence interval is 0.0049. There are 2 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 235 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000300589.6. 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.-8-2302T>C		intron	N/A	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.-58T>C		5_prime_UTR	Exon 1 of 12	NP_071445.1	Q9HC29-1
	NOD2	NR_163434.1		n.58-2302T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000300589.6	TSL:1	c.-58T>C		5_prime_UTR	Exon 1 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.-862T>C		5_prime_UTR	Exon 1 of 4	ENSP00000435149.2	E9PLF7
	NOD2	ENST00000647318.2	MANE Select	c.-8-2302T>C		intron	N/A	ENSP00000495993.1	Q9HC29-2

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 235 AN: 152212 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD4 exome AF: 0.000154 AC: 200 AN: 1295946 Hom.: 1 Cov.: 19 AF XY: 0.000127 AC XY: 82 AN XY: 644590

African (AFR) AF: 0.00605 AC: 178 AN: 29432

American (AMR) AF: 0.000309 AC: 11 AN: 35564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24534

East Asian (EAS) AF: 0.00 AC: 0 AN: 35328

South Asian (SAS) AF: 0.00 AC: 0 AN: 77078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4486

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 986040

Other (OTH) AF: 0.000183 AC: 10 AN: 54544

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152330 Hom.: 2 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74494

African (AFR) AF: 0.00548 AC: 228 AN: 41582

American (AMR) AF: 0.000196 AC: 3 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00194

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Blau syndrome (1)
-	-	1	Inflammatory bowel disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.4
DANN	Benign	0.51
PhyloP100		1.5
PromoterAI		-0.010	Neutral

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: rs139485985; hg19: chr16-50731097;