chr16-50697244-A-T

Variant names:

• chr16-50697244-A-T
• ENST00000527070.5:c.-804A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000527070.5(NOD2):​c.-804A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOD2 ENST00000527070.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.375
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

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.-8-2244A>T		intron	N/A	NP_001357395.1	Q9HC29-2
	NOD2	NM_022162.3		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 12	NP_071445.1	Q9HC29-1
	NOD2	NR_163434.1		n.58-2244A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000527070.5	TSL:1	c.-804A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000435149.2	E9PLF7
	NOD2	ENST00000300589.6	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 12	ENSP00000300589.2	Q9HC29-1
	NOD2	ENST00000527070.5	TSL:1	c.-804A>T		5_prime_UTR	Exon 1 of 4	ENSP00000435149.2	E9PLF7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403600 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 692818

African (AFR) AF: 0.00 AC: 0 AN: 31842

American (AMR) AF: 0.00 AC: 0 AN: 36350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 36180

South Asian (SAS) AF: 0.00 AC: 0 AN: 79452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081090

Other (OTH) AF: 0.00 AC: 0 AN: 58192

GnomAD4 genome Cov.: 32

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
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.071
DANN	Benign	0.88
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.052	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-1.1	T
PhyloP100		-0.38
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.27
MutPred		0.99		Gain of stability (P = 0.2932)
MVP		0.57
ClinPred		0.19	T
GERP RS		-4.0
PromoterAI		0.078	Neutral
Varity_R		0.69
gMVP		0.14

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: chr16-50731155;