8-89772790-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003821.6(RIPK2):​c.815G>A​(p.Gly272Glu) variant causes a missense change involving the alteration of a 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)

Consequence

RIPK2
NM_003821.6 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.43
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIPK2NM_003821.6 linkuse as main transcriptc.815G>A p.Gly272Glu missense_variant 6/11 ENST00000220751.5
RIPK2NM_001375360.1 linkuse as main transcriptc.404G>A p.Gly135Glu missense_variant 5/10
RIPK2XM_011517357.3 linkuse as main transcriptc.302G>A p.Gly101Glu missense_variant 4/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIPK2ENST00000220751.5 linkuse as main transcriptc.815G>A p.Gly272Glu missense_variant 6/111 NM_003821.6 P1O43353-1
RIPK2ENST00000522965.1 linkuse as main transcriptc.*454G>A 3_prime_UTR_variant, NMD_transcript_variant 5/101

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 11, 2022The c.815G>A (p.G272E) alteration is located in exon 6 (coding exon 6) of the RIPK2 gene. This alteration results from a G to A substitution at nucleotide position 815, causing the glycine (G) at amino acid position 272 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Benign
-0.45
T
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-3.8
D
REVEL
Uncertain
0.51
Sift
Benign
0.093
T
Sift4G
Uncertain
0.031
D
Polyphen
1.0
D
Vest4
0.95
MutPred
0.80
Gain of disorder (P = 0.0497);
MVP
0.75
MPC
0.83
ClinPred
0.99
D
GERP RS
6.1
Varity_R
0.67
gMVP
0.93

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.

Other links and lift over

dbSNP: rs1809336002; hg19: chr8-90785018; API