8-89772766-G-A

Position:

chr8-89772766-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_003821.6(RIPK2):c.791G>A(p.Arg264His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,611,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

RIPK2
NM_003821.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.11

Variant links:

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]

RIPK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09610295).

BP6

Variant 8-89772766-G-A is Benign according to our data. Variant chr8-89772766-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2411138.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RIPK2	NM_003821.6 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	6/11	ENST00000220751.5
RIPK2	NM_001375360.1 linkuse as main transcript	c.380G>A	p.Arg127His	missense_variant	5/10
RIPK2	XM_011517357.3 linkuse as main transcript	c.278G>A	p.Arg93His	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPK2	ENST00000220751.5 linkuse as main transcript	c.791G>A	p.Arg264His	missense_variant	6/11	1	NM_003821.6	P1	O43353-1
RIPK2	ENST00000522965.1 linkuse as main transcript	c.*430G>A		3_prime_UTR_variant, NMD_transcript_variant	5/10	1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

250132

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.000556

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1459768

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726228

show subpopulations

Gnomad4 AFR exome

AF:

0.000330

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000171

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000555

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000159

Hom.:

Bravo

AF:

0.000181

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.55

CADD

Benign

2.4

DANN

Benign

0.95

DEOGEN2

Benign

0.16

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.17

M_CAP

Benign

0.033

MetaRNN

Benign

0.096

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.040

REVEL

Benign

0.19

Sift

Benign

0.13

Sift4G

Benign

0.13

Polyphen

0.86

Vest4

0.081

MutPred

0.56

Loss of methylation at R264 (P = 0.0491);

MVP

0.59

MPC

0.47

ClinPred

0.034

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.18

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over