dbSNP rs104895421: NOD2:c.-8-7T>A (chr16-50699481-T-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001370466.1(NOD2):c.-8-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,612,234 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 18 hom. )

Consequence

NOD2
NM_001370466.1 splice_region, intron

Scores

Splicing: ADA: 0.002993

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: 1.40

Publications

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

NOD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 16-50699481-T-A is Benign according to our data. Variant chr16-50699481-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 97880.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00143 (217/152220) while in subpopulation AMR AF = 0.00248 (38/15302). AF 95% confidence interval is 0.00186. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 217 Unknown,AD gene.

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.-8-7T>A	splice_region intron	N/A	NP_001357395.1	Q9HC29-2
NOD2	NM_001293557.2		c.-15T>A	5_prime_UTR	Exon 1 of 11	NP_001280486.1	Q9HC29-2
NOD2	NM_022162.3		c.74-7T>A	splice_region intron	N/A	NP_071445.1	Q9HC29-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NOD2	ENST00000647318.2	MANE Select	c.-8-7T>A	splice_region intron	N/A	ENSP00000495993.1	Q9HC29-2
NOD2	ENST00000300589.6	TSL:1	c.74-7T>A	splice_region intron	N/A	ENSP00000300589.2	Q9HC29-1
NOD2	ENST00000527070.5	TSL:1	c.-8-7T>A	splice_region intron	N/A	ENSP00000435149.2	E9PLF7

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

217

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00249

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00231

AC:

577

AN:

249564

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.0000624

Gnomad AMR exome

AF:

0.00315

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.00589

GnomAD4 exome

AF:

0.00144

AC:

2109

AN:

1460014

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1068

AN XY:

726334

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

33432

American (AMR)

AF:

0.00286

AC:

128

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0274

AC:

715

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000325

AC:

AN:

86186

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.0177

AC:

AN:

4702

European-Non Finnish (NFE)

AF:

0.000810

AC:

900

AN:

1111540

Other (OTH)

AF:

0.00339

AC:

204

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

111

223

334

446

557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.00143

AC:

217

AN:

152220

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41542

American (AMR)

AF:

0.00248

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

68010

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00371

Hom.:

Bravo

AF:

0.00173

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autoinflammatory syndrome (1)

Blau syndrome (2)

Inflammatory bowel disease 1 (1)

not specified (1)

Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0030

dbscSNV1_RF

Benign

0.19

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over