rs61736932

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001370466.1(NOD2):​c.1752C>T​(p.Ala584=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,614,188 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 8 hom., cov: 33)
Exomes 𝑓: 0.011 ( 104 hom. )

Consequence

NOD2
NM_001370466.1 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.77
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 16-50711744-C-T is Benign according to our data. Variant chr16-50711744-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 319451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-50711744-C-T is described in Lovd as [Benign]. Variant chr16-50711744-C-T is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=-2.77 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00807 (1230/152358) while in subpopulation NFE AF= 0.0105 (713/68038). AF 95% confidence interval is 0.00984. There are 8 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOD2NM_001370466.1 linkuse as main transcriptc.1752C>T p.Ala584= synonymous_variant 4/12 ENST00000647318.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOD2ENST00000647318.2 linkuse as main transcriptc.1752C>T p.Ala584= synonymous_variant 4/12 NM_001370466.1 P1Q9HC29-2
NOD2ENST00000300589.6 linkuse as main transcriptc.1833C>T p.Ala611= synonymous_variant 4/121 Q9HC29-1
NOD2ENST00000641284.2 linkuse as main transcriptc.1752C>T p.Ala584= synonymous_variant, NMD_transcript_variant 4/6
NOD2ENST00000646677.2 linkuse as main transcriptc.1752C>T p.Ala584= synonymous_variant, NMD_transcript_variant 4/13

Frequencies

GnomAD3 genomes
AF:
0.00809
AC:
1231
AN:
152240
Hom.:
8
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00176
Gnomad AMI
AF:
0.0132
Gnomad AMR
AF:
0.00255
Gnomad ASJ
AF:
0.0323
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00269
Gnomad FIN
AF:
0.0234
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0105
Gnomad OTH
AF:
0.00907
GnomAD3 exomes
AF:
0.00967
AC:
2430
AN:
251352
Hom.:
15
AF XY:
0.00965
AC XY:
1311
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00148
Gnomad AMR exome
AF:
0.00214
Gnomad ASJ exome
AF:
0.0296
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00268
Gnomad FIN exome
AF:
0.0233
Gnomad NFE exome
AF:
0.0121
Gnomad OTH exome
AF:
0.0119
GnomAD4 exome
AF:
0.0110
AC:
16035
AN:
1461830
Hom.:
104
Cov.:
34
AF XY:
0.0108
AC XY:
7889
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00146
Gnomad4 AMR exome
AF:
0.00215
Gnomad4 ASJ exome
AF:
0.0316
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00327
Gnomad4 FIN exome
AF:
0.0220
Gnomad4 NFE exome
AF:
0.0116
Gnomad4 OTH exome
AF:
0.0107
GnomAD4 genome
AF:
0.00807
AC:
1230
AN:
152358
Hom.:
8
Cov.:
33
AF XY:
0.00862
AC XY:
642
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00176
Gnomad4 AMR
AF:
0.00255
Gnomad4 ASJ
AF:
0.0323
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00269
Gnomad4 FIN
AF:
0.0234
Gnomad4 NFE
AF:
0.0105
Gnomad4 OTH
AF:
0.00898
Alfa
AF:
0.0117
Hom.:
5
Bravo
AF:
0.00683
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00932
EpiControl
AF:
0.00931

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 23, 2023- -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024NOD2: BP4, BP7, BS1, BS2 -
not specified Benign:1
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Regional enteritis;C5201146:Blau syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Autoinflammatory syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenFeb 05, 2022- -
Inflammatory bowel disease 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Blau syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
-0.89
CADD
Benign
0.070
DANN
Benign
0.40

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs61736932; hg19: chr16-50745655; API