16-50712635-C-G

Variant names:

• chr16-50712635-C-G
• rs4785225
• ENST00000534067.5:n.*261C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000534067.5(NOD2):​n.*261C>G variant causes a splice region, non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 551,014 control chromosomes in the GnomAD database, including 105,205 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28758 hom., cov: 32)
  • Exomes 𝑓: 0.60 (76447 hom.)
• Consequence: NOD2 ENST00000534067.5 splice_region, non_coding_transcript_exon
• Scores: Splicing: ADA: 0.00004300
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.223
• Publications: 12 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)

ENSG00000270120 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-50712635-C-G is Benign according to our data. Variant chr16-50712635-C-G is described in ClinVar as Benign. ClinVar VariationId is 1237708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOD2	NM_001370466.1	c.2381+262C>G		intron_variant	Intron 4 of 11	ENST00000647318.2	NP_001357395.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOD2	ENST00000647318.2	c.2381+262C>G		intron_variant	Intron 4 of 11		NM_001370466.1	ENSP00000495993.1

Frequencies

GnomAD3 genomes AF: 0.605 AC: 91968 AN: 151922 Hom.: 28745 Cov.: 32

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.745

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.600 AC: 239544 AN: 398974 Hom.: 76447 Cov.: 3 AF XY: 0.589 AC XY: 123154 AN XY: 208990

African (AFR) AF: 0.596 AC: 6826 AN: 11446

American (AMR) AF: 0.504 AC: 8459 AN: 16794

Ashkenazi Jewish (ASJ) AF: 0.786 AC: 9859 AN: 12536

East Asian (EAS) AF: 0.226 AC: 6089 AN: 26952

South Asian (SAS) AF: 0.395 AC: 16858 AN: 42688

European-Finnish (FIN) AF: 0.577 AC: 14340 AN: 24852

Middle Eastern (MID) AF: 0.686 AC: 1228 AN: 1790

European-Non Finnish (NFE) AF: 0.677 AC: 161550 AN: 238520

Other (OTH) AF: 0.613 AC: 14335 AN: 23396

GnomAD4 genome AF: 0.605 AC: 92025 AN: 152040 Hom.: 28758 Cov.: 32 AF XY: 0.596 AC XY: 44259 AN XY: 74312

African (AFR) AF: 0.586 AC: 24300 AN: 41452

American (AMR) AF: 0.564 AC: 8620 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2685 AN: 3466

East Asian (EAS) AF: 0.193 AC: 1001 AN: 5176

South Asian (SAS) AF: 0.348 AC: 1675 AN: 4818

European-Finnish (FIN) AF: 0.569 AC: 6003 AN: 10558

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45562 AN: 67972

Other (OTH) AF: 0.619 AC: 1307 AN: 2112

Alfa AF: 0.509 Hom.: 1429

Bravo AF: 0.605

Asia WGS AF: 0.294 AC: 1028 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jan 24, 2024

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 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.49
PhyloP100		-0.22
PromoterAI		-0.079	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000043
dbscSNV1_RF	Benign	0.12
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: rs4785225; hg19: chr16-50746546;