8-89762965-A-G

Variant names:

• chr8-89762965-A-G
• rs200818100
• NM_003821.6:c.310A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003821.6(RIPK2):​c.310A>G​(p.Asn104Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000561 in 1,505,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: RIPK2 NM_003821.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.15

Genes affected

RIPK2 (HGNC:10020): (receptor interacting serine/threonine kinase 2) This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein contains a C-terminal caspase activation and recruitment domain (CARD), and is a component of signaling complexes in both the innate and adaptive immune pathways. It is a potent activator of NF-kappaB and inducer of apoptosis in response to various stimuli. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.058858544).
• BS2: High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK2	NM_003821.6	c.310A>G	p.Asn104Asp	missense_variant	Exon 2 of 11	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1	c.-84-2376A>G		intron_variant	Intron 1 of 9		NP_001362289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5	c.310A>G	p.Asn104Asp	missense_variant	Exon 2 of 11	1	NM_003821.6	ENSP00000220751.4
RIPK2	ENST00000522965.1	n.174-2376A>G		intron_variant	Intron 1 of 9	1		ENSP00000429271.1
RIPK2	ENST00000517696.1	n.*222A>G		downstream_gene_variant		4		ENSP00000427736.1

Frequencies

GnomAD3 genomes AF: 0.000420 AC: 64 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000466 AC: 101 AN: 216688 AF XY: 0.000424

Gnomad AFR exome AF: 0.0000682

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000383

Gnomad NFE exome AF: 0.000792

Gnomad OTH exome AF: 0.000397

GnomAD4 exome AF: 0.000576 AC: 780 AN: 1353102 Hom.: 0 Cov.: 28 AF XY: 0.000526 AC XY: 350 AN XY: 665460

Gnomad4 AFR exome AF: 0.0000975 AC: 3 AN: 30758

Gnomad4 AMR exome AF: 0.000168 AC: 6 AN: 35612

Gnomad4 ASJ exome AF: 0.0000850 AC: 2 AN: 23534

Gnomad4 EAS exome AF: 0.0000269 AC: 1 AN: 37130

Gnomad4 SAS exome AF: 0.000244 AC: 16 AN: 65694

Gnomad4 FIN exome AF: 0.000700 AC: 35 AN: 50008

Gnomad4 NFE exome AF: 0.000660 AC: 693 AN: 1049666

Gnomad4 Remaining exome AF: 0.000416 AC: 23 AN: 55310

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74476

Gnomad4 AFR AF: 0.000120 AC: 0.000120244 AN: 0.000120244

Gnomad4 AMR AF: 0.000131 AC: 0.000130719 AN: 0.000130719

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.000471 AC: 0.00047081 AN: 0.00047081

Gnomad4 NFE AF: 0.000750 AC: 0.000749868 AN: 0.000749868

Gnomad4 OTH AF: 0.000473 AC: 0.000473485 AN: 0.000473485

Alfa AF: 0.000757 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RIPK2: PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.33	N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.14
Sift	Benign	0.40	T
Sift4G	Benign	0.99	T
Polyphen		0.13	B
Vest4		0.22
MVP		0.73
MPC		1.4
ClinPred		0.030	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.60
Mutation Taster		=26/74	disease causing

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

LitVar

Other links and lift over

dbSNP: rs200818100; hg19: chr8-90775193;