rs2076756

Variant names:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received -16 ACMG points: 0P and 16B. BA1BP4_StrongBP6_Strong

The NM_001370466.1(NOD2):c.2717+265A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.171 (AC=26,017) in the gnomAD database across 151,902 control chromosomes, including 2,890 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.251. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2890 hom., cov: 31)

Consequence

NOD2
NM_001370466.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.293

Publications

99 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Illumina, Genomics England PanelApp, Orphanet, ClinGen
inflammatory bowel disease 1
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NOD2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001370466.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2508 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370466.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOD2	NM_001370466.1	MANE Select	c.2717+265A>G	intron	N/A	NP_001357395.1	Q9HC29-2
NOD2	NM_022162.3		c.2798+265A>G	intron	N/A	NP_071445.1	Q9HC29-1
NOD2	NM_001293557.2		c.2717+265A>G	intron	N/A	NP_001280486.1	Q9HC29-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOD2	ENST00000647318.2	MANE Select	c.2717+265A>G	intron	N/A	ENSP00000495993.1	Q9HC29-2
NOD2	ENST00000300589.6	TSL:1	c.2798+265A>G	intron	N/A	ENSP00000300589.2	Q9HC29-1
NOD2	ENST00000534057.1	TSL:1	c.431+265A>G	intron	N/A	ENSP00000437246.1	H0YF53

Frequencies

GnomAD3 genomes

AF:

0.171

AC:

26009

AN:

151784

Hom.:

2889

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0600

Gnomad AMI

AF:

0.305

Gnomad AMR

AF:

0.159

Gnomad ASJ

AF:

0.235

Gnomad EAS

AF:

0.00813

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.153

Gnomad MID

AF:

0.236

Gnomad NFE

AF:

0.254

Gnomad OTH

AF:

0.203

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.171

AC:

26017

AN:

151902

Hom.:

2890

Cov.:

AF XY:

0.166

AC XY:

12342

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.0601

AC:

2489

AN:

41430

American (AMR)

AF:

0.159

AC:

2427

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.235

AC:

813

AN:

3462

East Asian (EAS)

AF:

0.00815

AC:

AN:

5152

South Asian (SAS)

AF:

0.128

AC:

616

AN:

4800

European-Finnish (FIN)

AF:

0.153

AC:

1611

AN:

10556

Middle Eastern (MID)

AF:

0.223

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.254

AC:

17247

AN:

67920

Other (OTH)

AF:

0.204

AC:

429

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1015

2029

3044

4058

5073

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

278

556

834

1112

1390

<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:

0.227

Hom.:

18854

Bravo

AF:

0.165

Asia WGS

AF:

0.0730

AC:

260

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.000606

AC:

AN:

122212

Turkish Variome

AF:

0.238

AC:

367

AN:

1542

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.00692

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.209

AC:

489

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.29

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over