rs3135500

chr16-50732975-G-Achr16-50732975-G-C

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.*1156G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 152,212 control chromosomes in the GnomAD database, including 15,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15031 hom., cov: 34)
  • Exomes 𝑓: 0.47 (18 hom.)
• Consequence: NOD2 NM_001370466.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.245

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=-0.91).
• BP6: Variant 16-50732975-G-A is Benign according to our data. Variant chr16-50732975-G-A is described in ClinVar as [Benign]. Clinvar id is 319492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.*1156G>A		3_prime_UTR_variant	12/12	ENST00000647318.2
CYLD-AS1	NR_184279.1	n.270-615C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.*1156G>A		3_prime_UTR_variant	12/12		NM_001370466.1	P1
CYLD-AS1	ENST00000563315.2	n.871-615C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66064 AN: 151958 Hom.: 14997 Cov.: 34

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.524

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.410

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.407

GnomAD4 exome AF: 0.471 AC: 64 AN: 136 Hom.: 18 Cov.: 0 AF XY: 0.500 AC XY: 38 AN XY: 76

Gnomad4 EAS exome AF: 0.471

GnomAD4 genome AF: 0.435 AC: 66155 AN: 152076 Hom.: 15031 Cov.: 34 AF XY: 0.430 AC XY: 31955 AN XY: 74326

Gnomad4 AFR AF: 0.557

Gnomad4 AMR AF: 0.402

Gnomad4 ASJ AF: 0.524

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.410

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.403

Alfa AF: 0.399 Hom.: 13296

Bravo AF: 0.440

Asia WGS AF: 0.231 AC: 803 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoinflammatory syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 05, 2022

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.63
Dann	Benign	0.46

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: rs3135500; hg19: chr16-50766886;