8-89786627-G-C

Position:

• chr8-89786627-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003821.6(RIPK2):​c.1064G>C​(p.Ser355Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 30)
• Consequence: RIPK2 NM_003821.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.335

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047544092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RIPK2	NM_003821.6	c.1064G>C	p.Ser355Thr	missense_variant	9/11	ENST00000220751.5
RIPK2	NM_001375360.1	c.653G>C	p.Ser218Thr	missense_variant	8/10
RIPK2	XM_011517357.3	c.551G>C	p.Ser184Thr	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RIPK2	ENST00000220751.5	c.1064G>C	p.Ser355Thr	missense_variant	9/11	1	NM_003821.6	P1
RIPK2	ENST00000522965.1	c.*703G>C		3_prime_UTR_variant, NMD_transcript_variant	8/10	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.1064G>C (p.S355T) alteration is located in exon 9 (coding exon 9) of the RIPK2 gene. This alteration results from a G to C substitution at nucleotide position 1064, causing the serine (S) at amino acid position 355 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	0.062
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.5
DANN	Benign	0.73
DEOGEN2	Benign	0.076	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.42	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.12
Sift	Benign	0.41	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.055
MutPred		0.11		Loss of phosphorylation at S355 (P = 0.0553);
MVP		0.32
MPC		0.17
ClinPred		0.019	T
GERP RS		2.5
Varity_R		0.029
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-90798855;