rs104895436

chr16-50711578-GGGGCCT-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM4 PP3

The NM_001370466.1(NOD2):c.1591_1596del(p.Leu531_Gly532del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,532 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NOD2 NM_001370466.1 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 8.91

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001370466.1.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.1591_1596del	p.Leu531_Gly532del	inframe_deletion	4/12	ENST00000647318.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.1591_1596del	p.Leu531_Gly532del	inframe_deletion	4/12		NM_001370466.1	P1
NOD2	ENST00000300589.6	c.1672_1677del	p.Leu558_Gly559del	inframe_deletion	4/12	1
NOD2	ENST00000641284.2	c.1591_1596del	p.Leu531_Gly532del	inframe_deletion, NMD_transcript_variant	4/6
NOD2	ENST00000646677.2	c.1591_1596del	p.Leu531_Gly532del	inframe_deletion, NMD_transcript_variant	4/13

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249118 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459532 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 726162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 22, 2023

In-frame deletion of 2 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11875755) -

Regional enteritis;C5201146:Blau syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 20, 2022

This variant has been observed in individual(s) with Crohn's disease (PMID: 11875755). This variant is present in population databases (rs779106464, gnomAD 0.003%). This variant, c.1672_1677del, results in the deletion of 2 amino acid(s) of the NOD2 protein (p.Leu558_Gly559del), but otherwise preserves the integrity of the reading frame. This variant is also known as c.1671delCCTGGG. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 97837). -

Blau syndrome Other:1

not provided, no classification provided

literature only

Unité médicale des maladies autoinflammatoires, CHRU Montpellier

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104895436; hg19: chr16-50745489;