16-50711539-G-C

Variant names:

• chr16-50711539-G-C
• rs772534917
• NM_001370466.1:c.1547G>C

Variant summary

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

The NM_001370466.1(NOD2):​c.1547G>C​(p.Arg516Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,326 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOD2 NM_001370466.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53

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=0.24255985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.1547G>C	p.Arg516Pro	missense_variant	Exon 4 of 12	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.1547G>C	p.Arg516Pro	missense_variant	Exon 4 of 12		NM_001370466.1	ENSP00000495993.1
NOD2	ENST00000300589.6	c.1628G>C	p.Arg543Pro	missense_variant	Exon 4 of 12	1		ENSP00000300589.2
NOD2	ENST00000641284.2	n.1547G>C		non_coding_transcript_exon_variant	Exon 4 of 6			ENSP00000493088.1
NOD2	ENST00000646677.2	n.1547G>C		non_coding_transcript_exon_variant	Exon 4 of 13			ENSP00000496533.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249464 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS 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: 6.85e-7 AC: 1 AN: 1460326 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.23	.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	.;N
REVEL	Uncertain	0.40
Sift	Benign	0.079	.;T
Sift4G	Benign	0.11	.;T
Polyphen		0.92	P;D
Vest4		0.43
MutPred		0.60		.;Gain of glycosylation at R543 (P = 0.0252);
MVP		0.78
MPC		0.32
ClinPred		0.18	T
GERP RS		3.0
Varity_R		0.30
gMVP		0.71

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: rs772534917; hg19: chr16-50745450;