16-50699463-G-T

Variant names:

• chr16-50699463-G-T
• rs2076753
• NM_001370466.1:c.-8-25G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001370466.1(NOD2):​c.-8-25G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,603,308 control chromosomes in the GnomAD database, including 55,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3671 hom., cov: 31)
  • Exomes 𝑓: 0.26 (51718 hom.)
• Consequence: NOD2 NM_001370466.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.412
• Publications: 14 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: ClinGen, Orphanet, Genomics England PanelApp, G2P, Illumina, Labcorp Genetics (formerly Invitae)
• inflammatory bowel disease 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-50699463-G-T is Benign according to our data. Variant chr16-50699463-G-T is described in ClinVar as Benign. ClinVar VariationId is 2628228.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370466.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	NM_001370466.1	MANE Select	c.-8-25G>T		intron	N/A	NP_001357395.1
	NOD2	NM_001293557.2		c.-33G>T		5_prime_UTR	Exon 1 of 11	NP_001280486.1
	NOD2	NM_022162.3		c.74-25G>T		intron	N/A	NP_071445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOD2	ENST00000647318.2	MANE Select	c.-8-25G>T		intron	N/A	ENSP00000495993.1
	NOD2	ENST00000300589.6	TSL:1	c.74-25G>T		intron	N/A	ENSP00000300589.2
	NOD2	ENST00000527070.5	TSL:1	c.-8-25G>T		intron	N/A	ENSP00000435149.2

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29637 AN: 151920 Hom.: 3670 Cov.: 31

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.235

Gnomad EAS AF: 0.00889

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.231

GnomAD2 exomes AF: 0.201 AC: 49930 AN: 248254 AF XY: 0.209

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.00637

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.284

Gnomad OTH exome AF: 0.241

GnomAD4 exome AF: 0.255 AC: 370354 AN: 1451270 Hom.: 51718 Cov.: 30 AF XY: 0.254 AC XY: 183388 AN XY: 722426

African (AFR) AF: 0.0674 AC: 2239 AN: 33222

American (AMR) AF: 0.136 AC: 6088 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 6282 AN: 26058

East Asian (EAS) AF: 0.00353 AC: 140 AN: 39660

South Asian (SAS) AF: 0.156 AC: 13391 AN: 85964

European-Finnish (FIN) AF: 0.193 AC: 10262 AN: 53210

Middle Eastern (MID) AF: 0.277 AC: 1197 AN: 4322

European-Non Finnish (NFE) AF: 0.287 AC: 316972 AN: 1104178

Other (OTH) AF: 0.230 AC: 13783 AN: 59956

GnomAD4 genome AF: 0.195 AC: 29645 AN: 152038 Hom.: 3671 Cov.: 31 AF XY: 0.190 AC XY: 14152 AN XY: 74318

African (AFR) AF: 0.0727 AC: 3015 AN: 41500

American (AMR) AF: 0.190 AC: 2897 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 813 AN: 3464

East Asian (EAS) AF: 0.00891 AC: 46 AN: 5160

South Asian (SAS) AF: 0.134 AC: 644 AN: 4818

European-Finnish (FIN) AF: 0.191 AC: 2021 AN: 10566

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19342 AN: 67942

Other (OTH) AF: 0.232 AC: 490 AN: 2110

Alfa AF: 0.186 Hom.: 799

Bravo AF: 0.188

Asia WGS AF: 0.0750 AC: 268 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 33% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.3
DANN	Benign	0.81
PhyloP100		0.41
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs2076753; hg19: chr16-50733374;