chr16-50697275-A-T

Variant names:

• chr16-50697275-A-T
• rs754538287
• ENST00000527070.5:c.-773A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The ENST00000527070.5(NOD2):​c.-773A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,408,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: NOD2 ENST00000527070.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.64
• 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: 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: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059592962).
• BS2: High AC in GnomAdExome4 at 5 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000527070.5. 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.-8-2213A>T		intron	N/A	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.32A>T	p.Asp11Val	missense	Exon 1 of 12	NP_071445.1	Q9HC29-1
	NOD2	NR_163434.1		n.58-2213A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000527070.5	TSL:1	c.-773A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000435149.2	E9PLF7
	NOD2	ENST00000300589.6	TSL:1	c.32A>T	p.Asp11Val	missense	Exon 1 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.-773A>T		5_prime_UTR	Exon 1 of 4	ENSP00000435149.2	E9PLF7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 171140 AF XY: 0.00

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: 0.0000288

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1408146 Hom.: 0 Cov.: 31 AF XY: 0.00000719 AC XY: 5 AN XY: 695434

African (AFR) AF: 0.00 AC: 0 AN: 32054

American (AMR) AF: 0.00 AC: 0 AN: 37124

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25246

East Asian (EAS) AF: 0.00 AC: 0 AN: 36556

South Asian (SAS) AF: 0.00 AC: 0 AN: 79752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000369 AC: 4 AN: 1083472

Other (OTH) AF: 0.00 AC: 0 AN: 58374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000868 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Regional enteritis;C5201146:Blau syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.012
DANN	Benign	0.57
DEOGEN2	Benign	0.071	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.092
Sift	Pathogenic	0.0	D
Polyphen		0.012	B
Vest4		0.12
MutPred		0.11		Gain of helix (P = 0.0199)
MVP		0.50
MPC		0.22
ClinPred		0.12	T
GERP RS		-3.3
PromoterAI		-0.052	Neutral
Varity_R		0.12
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs754538287; hg19: chr16-50731186;