8-89772762-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003821.6(RIPK2):​c.787G>A​(p.Ala263Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,926 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RIPK2
NM_003821.6 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.094168454).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RIPK2NM_003821.6 linkuse as main transcriptc.787G>A p.Ala263Thr missense_variant 6/11 ENST00000220751.5
RIPK2NM_001375360.1 linkuse as main transcriptc.376G>A p.Ala126Thr missense_variant 5/10
RIPK2XM_011517357.3 linkuse as main transcriptc.274G>A p.Ala92Thr missense_variant 4/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RIPK2ENST00000220751.5 linkuse as main transcriptc.787G>A p.Ala263Thr missense_variant 6/111 NM_003821.6 P1O43353-1
RIPK2ENST00000522965.1 linkuse as main transcriptc.*426G>A 3_prime_UTR_variant, NMD_transcript_variant 5/101

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
250312
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135290
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1459926
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
726312
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
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 GeneticsApr 22, 2022The c.787G>A (p.A263T) 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 787, causing the alanine (A) at amino acid position 263 to be replaced by a threonine (T). 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
Benign
0.068
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
5.1
DANN
Benign
0.91
DEOGEN2
Benign
0.17
T
Eigen
Benign
-0.79
Eigen_PC
Benign
-0.69
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.094
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-0.53
N
REVEL
Benign
0.015
Sift
Benign
0.32
T
Sift4G
Benign
0.61
T
Polyphen
0.0090
B
Vest4
0.076
MutPred
0.32
Loss of methylation at R264 (P = 0.168);
MVP
0.48
MPC
0.18
ClinPred
0.015
T
GERP RS
2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.074
gMVP
0.18

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: rs1420296684; hg19: chr8-90784990; API