8-89789324-A-C

Position:

• chr8-89789324-A-C

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

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 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	UniProt
RIPK2	NM_003821.6	c.1127A>C	p.Lys376Thr	missense_variant	10/11	ENST00000220751.5
RIPK2	NM_001375360.1	c.716A>C	p.Lys239Thr	missense_variant	9/10
RIPK2	XM_011517357.3	c.614A>C	p.Lys205Thr	missense_variant	8/9

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460472 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726494

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.: 32

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.53
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.14
Sift	Benign	0.38	T
Sift4G	Benign	0.54	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.32		Loss of ubiquitination at K376 (P = 0.003);
MVP		0.47
MPC		0.24
ClinPred		0.046	T
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.

Other links and lift over

hg19: chr8-90801552;