chr16-50697256-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022162.3(NOD2):​c.13G>T​(p.Gly5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,405,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G5R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: NOD2 NM_022162.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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: Labcorp Genetics (formerly Invitae), Illumina, G2P, Genomics England PanelApp, Orphanet, ClinGen
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.053111702).
• BS2: High AC in GnomAdExome4 at 7 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022162.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.-8-2232G>T		intron	N/A	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.13G>T	p.Gly5Cys	missense	Exon 1 of 12	NP_071445.1	Q9HC29-1
	NOD2	NR_163434.1		n.58-2232G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000300589.6	TSL:1	c.13G>T	p.Gly5Cys	missense	Exon 1 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.-792G>T		5_prime_UTR	Exon 1 of 4	ENSP00000435149.2	E9PLF7
	NOD2	ENST00000647318.2	MANE Select	c.-8-2232G>T		intron	N/A	ENSP00000495993.1	Q9HC29-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000596 AC: 1 AN: 167788 AF XY: 0.0000113

Gnomad AFR exome AF: 0.00

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: 0.00000498 AC: 7 AN: 1405840 Hom.: 0 Cov.: 31 AF XY: 0.00000720 AC XY: 5 AN XY: 694102

African (AFR) AF: 0.00 AC: 0 AN: 31946

American (AMR) AF: 0.00 AC: 0 AN: 36686

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

East Asian (EAS) AF: 0.0000550 AC: 2 AN: 36354

South Asian (SAS) AF: 0.0000377 AC: 3 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: 0.00 AC: 0 AN: 58278

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	1.1
DANN	Benign	0.85
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.17
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.17		Loss of relative solvent accessibility (P = 0.0306)
MVP		0.66
MPC		0.27
ClinPred		0.19	T
GERP RS		-0.61
PromoterAI		-0.027	Neutral
Varity_R		0.20
gMVP		0.091

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;