rs5743276

Positions:

• chr16-50711961-C-G
• chr16-50711961-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370466.1(NOD2):​c.1969C>G​(p.Arg657Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R657W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15937418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.1969C>G	p.Arg657Gly	missense_variant	4/12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.1969C>G	p.Arg657Gly	missense_variant	4/12		NM_001370466.1	ENSP00000495993	P1
NOD2	ENST00000300589.6	c.2050C>G	p.Arg684Gly	missense_variant	4/12	1		ENSP00000300589
NOD2	ENST00000641284.2	c.1969C>G	p.Arg657Gly	missense_variant, NMD_transcript_variant	4/6			ENSP00000493088
NOD2	ENST00000646677.2	c.1969C>G	p.Arg657Gly	missense_variant, NMD_transcript_variant	4/13			ENSP00000496533

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460814 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726632

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T;T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	.;L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.094
Sift	Benign	0.12	.;T
Sift4G	Benign	0.17	.;T
Polyphen		0.0040	B;B
Vest4		0.20
MutPred		0.53		.;Gain of glycosylation at S683 (P = 0.1082);
MVP		0.79
MPC		0.12
ClinPred		0.048	T
GERP RS		1.3
Varity_R		0.081
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs5743276; hg19: chr16-50745872;