16-50697245-T-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PVS1_SupportingBS2

The ENST00000300589.6(NOD2):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000122 in 1,555,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

NOD2
ENST00000300589.6 start_lost

Scores

2
1
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.26

Publications

1 publications found
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]
NOD2 Gene-Disease associations (from GenCC):
  • Blau syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
  • inflammatory bowel disease 1
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 28 codons. Genomic position: 50699496. Lost 0.026 part of the original CDS.
BS2
High AC in GnomAd4 at 15 AD,Unknown gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NOD2NM_001370466.1 linkc.-8-2243T>C intron_variant Intron 1 of 11 ENST00000647318.2 NP_001357395.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NOD2ENST00000647318.2 linkc.-8-2243T>C intron_variant Intron 1 of 11 NM_001370466.1 ENSP00000495993.1 Q9HC29-2

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000243
AC:
4
AN:
164794
AF XY:
0.0000115
show subpopulations
Gnomad AFR exome
AF:
0.000317
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000152
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000285
AC:
4
AN:
1403858
Hom.:
0
Cov.:
31
AF XY:
0.00000289
AC XY:
2
AN XY:
692952
show subpopulations
African (AFR)
AF:
0.0000628
AC:
2
AN:
31854
American (AMR)
AF:
0.00
AC:
0
AN:
36378
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25218
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36206
South Asian (SAS)
AF:
0.00
AC:
0
AN:
79458
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5676
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1081256
Other (OTH)
AF:
0.0000344
AC:
2
AN:
58198
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000986
AC:
15
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000942
AC XY:
7
AN XY:
74306
show subpopulations
African (AFR)
AF:
0.000314
AC:
13
AN:
41426
American (AMR)
AF:
0.000131
AC:
2
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10612
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68014
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.462
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000988
Hom.:
0
Bravo
AF:
0.0000945
ExAC
AF:
0.00000884
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Regional enteritis;C5201146:Blau syndrome Uncertain:1
May 14, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change affects the initiator methionine of the NOD2 mRNA. The next in-frame methionine is located at codon 28. This variant is present in population databases (rs765406921, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with NOD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 531595). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Benign
-0.30
CADD
Benign
5.8
DANN
Benign
0.82
DEOGEN2
Benign
0.072
T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.14
N
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.029
D
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-1.0
T
PhyloP100
1.3
PROVEAN
Benign
-0.17
N
REVEL
Benign
0.22
Sift
Pathogenic
0.0
D
Polyphen
0.0020
B
Vest4
0.47
MVP
0.64
ClinPred
0.088
T
GERP RS
-4.3
PromoterAI
0.054
Neutral
Varity_R
0.59
gMVP
0.23

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

Other links and lift over

dbSNP: rs765406921; hg19: chr16-50731156; API