chr16-50697262-T-G

Variant names:

• chr16-50697262-T-G
• ENST00000300589.6:c.19T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001370466.1(NOD2):​c.-8-2226T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NOD2 NM_001370466.1 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.141
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05253485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.-8-2226T>G		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.-8-2226T>G		intron_variant	Intron 1 of 11		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19T>G (p.S7A) alteration is located in exon 1 (coding exon 1) of the NOD2 gene. This alteration results from a T to G substitution at nucleotide position 19, causing the serine (S) at amino acid position 7 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.9
DANN	Benign	0.56
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.14
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.16
Sift	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.088
MutPred		0.14		Loss of phosphorylation at S7 (P = 0.0093);
MVP		0.56
MPC		0.078
ClinPred		0.16	T
GERP RS		-0.0089
PromoterAI		-0.046	Neutral
Varity_R		0.057
gMVP		0.080

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

hg19: chr16-50731173;