16-50697256-G-C

Variant names:

• chr16-50697256-G-C
• rs140977130
• ENST00000300589.6:c.13G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001370466.1(NOD2):​c.-8-2232G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000764 in 1,558,032 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: NOD2 NM_001370466.1 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.172
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009373516).
• BP6: Variant 16-50697256-G-C is Benign according to our data. Variant chr16-50697256-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 732125.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000348 (53/152192) while in subpopulation AFR AF = 0.00121 (50/41450). AF 95% confidence interval is 0.00094. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 53 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.-8-2232G>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
NOD2	ENST00000647318.2	c.-8-2232G>C		intron_variant	Intron 1 of 11		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00121

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: 0.000478

GnomAD2 exomes AF: 0.000119 AC: 20 AN: 167788 AF XY: 0.0000451

Gnomad AFR exome AF: 0.00206

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000469 AC: 66 AN: 1405840 Hom.: 0 Cov.: 31 AF XY: 0.0000375 AC XY: 26 AN XY: 694102

African (AFR) AF: 0.00178 AC: 57 AN: 31946

American (AMR) AF: 0.0000545 AC: 2 AN: 36686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 36354

South Asian (SAS) AF: 0.00 AC: 0 AN: 79580

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1082358

Other (OTH) AF: 0.0000858 AC: 5 AN: 58278

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74346

African (AFR) AF: 0.00121 AC: 50 AN: 41450

American (AMR) AF: 0.000131 AC: 2 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.00160 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000436 AC: 5

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Regional enteritis;C5201146:Blau syndrome Benign:1

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.2
DANN	Benign	0.78
DEOGEN2	Benign	0.069	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.17
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Polyphen		0.089	B
Vest4		0.087
MVP		0.66
MPC		0.22
ClinPred		0.10	T
GERP RS		-0.61
PromoterAI		-0.031	Neutral
Varity_R		0.099
gMVP		0.058

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

Other links and lift over

dbSNP: rs140977130; hg19: chr16-50731167;