16-50729826-A-G

Position:

• chr16-50729826-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001370466.1(NOD2):​c.2894A>G​(p.Asn965Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.03

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]

CYLD-AS1 (HGNC:55352): (CYLD antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3194872).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOD2	NM_001370466.1	c.2894A>G	p.Asn965Ser	missense_variant	11/12	ENST00000647318.2
CYLD-AS1	NR_184279.1	n.523+17T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOD2	ENST00000647318.2	c.2894A>G	p.Asn965Ser	missense_variant	11/12		NM_001370466.1	P1
CYLD-AS1	ENST00000563315.2	n.1124+17T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.2975A>G (p.N992S) alteration is located in exon 11 (coding exon 11) of the NOD2 gene. This alteration results from a A to G substitution at nucleotide position 2975, causing the asparagine (N) at amino acid position 992 to be replaced by a serine (S). 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	0.091
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.060	.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.92	.;L
MutationTaster	Benign	0.73	N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.49	.;N
REVEL	Benign	0.14
Sift	Benign	0.036	.;D
Sift4G	Benign	0.26	.;T
Polyphen		1.0	.;D
Vest4		0.44
MutPred		0.36		.;Gain of disorder (P = 0.0752);
MVP		0.79
MPC		0.16
ClinPred		0.69	D
GERP RS		5.6
Varity_R		0.059
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-50763737;