Variant chr8-89789324-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003821.6(RIPK2):c.1127A>C(p.Lys376Thr) 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 1,460,472 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: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RIPK2
NM_003821.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.84

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RIPK2	NM_003821.6 linkuse as main transcript	c.1127A>C	p.Lys376Thr	missense_variant	10/11	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1 linkuse as main transcript	c.716A>C	p.Lys239Thr	missense_variant	9/10		NP_001362289.1
RIPK2	XM_011517357.3 linkuse as main transcript	c.614A>C	p.Lys205Thr	missense_variant	8/9		XP_011515659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5 linkuse as main transcript	c.1127A>C	p.Lys376Thr	missense_variant	10/11	1	NM_003821.6	ENSP00000220751	P1	O43353-1
RIPK2	ENST00000522965.1 linkuse as main transcript	c.*766A>C		3_prime_UTR_variant, NMD_transcript_variant	9/10	1		ENSP00000429271

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460472

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726494

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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 submitter

clinical testing

Ambry Genetics

Jun 10, 2024

The c.1127A>C (p.K376T) alteration is located in exon 10 (coding exon 10) of the RIPK2 gene. This alteration results from a A to C substitution at nucleotide position 1127, causing the lysine (K) at amino acid position 376 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

0.080

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.53

DEOGEN2

Benign

0.13

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.56

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.64

M_CAP

Benign

0.022

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.030

REVEL

Benign

0.14

Sift

Benign

0.38

Sift4G

Benign

0.54

Polyphen

0.0010

Vest4

0.27

MutPred

0.32

Loss of ubiquitination at K376 (P = 0.003);

MVP

0.47

MPC

0.24

ClinPred

0.046

GERP RS

3.5

Varity_R

0.035

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.29

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over