rs3135499

Positions:

• chr16-50732216-A-C
• chr16-50732216-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370466.1(NOD2):​c.*397A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 353,018 control chromosomes in the GnomAD database, including 30,965 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15644 hom., cov: 30)
  • Exomes 𝑓: 0.38 (15321 hom.)
• Consequence: NOD2 NM_001370466.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.931

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]

CYLD-AS1 (HGNC:55352): (CYLD antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 16-50732216-A-C is Benign according to our data. Variant chr16-50732216-A-C is described in ClinVar as [Benign]. Clinvar id is 319482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.*397A>C		3_prime_UTR_variant	12/12	ENST00000647318.2	NP_001357395.1
CYLD-AS1	NR_184279.1	n.412+2T>G		splice_donor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.*397A>C		3_prime_UTR_variant	12/12		NM_001370466.1	ENSP00000495993	P1
CYLD-AS1	ENST00000563315.2	n.1013+2T>G		splice_donor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.445 AC: 67416 AN: 151636 Hom.: 15619 Cov.: 30

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.377 AC: 75867 AN: 201264 Hom.: 15321 Cov.: 0 AF XY: 0.363 AC XY: 39328 AN XY: 108376

Gnomad4 AFR exome AF: 0.561

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.427

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.399

GnomAD4 genome AF: 0.445 AC: 67495 AN: 151754 Hom.: 15644 Cov.: 30 AF XY: 0.440 AC XY: 32618 AN XY: 74162

Gnomad4 AFR AF: 0.556

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.532

Gnomad4 EAS AF: 0.189

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.419

Gnomad4 OTH AF: 0.411

Alfa AF: 0.417 Hom.: 27852

Bravo AF: 0.448

Asia WGS AF: 0.235 AC: 816 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Inflammatory bowel disease 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Blau syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Leprosy, susceptibility to, 1 Other:1

Uncertain risk allele, no assertion criteria provided

case-control

Centro Dermatológico Federico Lleras Acosta, Hospital Universitario Centro Dermatológico Federico Lleras Acosta

Jun 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	9.3
DANN	Benign	0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs3135499; hg19: chr16-50766127; COSMIC: COSV56051520; COSMIC: COSV56051520;