8-89772777-C-G

Position:

• chr8-89772777-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003821.6(RIPK2):​c.802C>G​(p.Leu268Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,610,338 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0074 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (16 hom.)
• Consequence: RIPK2 NM_003821.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013203502).
• BP6: Variant 8-89772777-C-G is Benign according to our data. Variant chr8-89772777-C-G is described in ClinVar as [Benign]. Clinvar id is 791293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00736 (1119/152086) while in subpopulation AFR AF= 0.0255 (1059/41492). AF 95% confidence interval is 0.0242. There are 12 homozygotes in gnomad4. There are 508 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RIPK2	NM_003821.6	c.802C>G	p.Leu268Val	missense_variant	6/11	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1	c.391C>G	p.Leu131Val	missense_variant	5/10		NP_001362289.1
RIPK2	XM_011517357.3	c.289C>G	p.Leu97Val	missense_variant	4/9		XP_011515659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5	c.802C>G	p.Leu268Val	missense_variant	6/11	1	NM_003821.6	ENSP00000220751	P1
RIPK2	ENST00000522965.1	c.*441C>G		3_prime_UTR_variant, NMD_transcript_variant	5/10	1		ENSP00000429271

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1118 AN: 151968 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00183 AC: 456 AN: 248534 Hom.: 6 AF XY: 0.00133 AC XY: 179 AN XY: 134332

Gnomad AFR exome AF: 0.0256

Gnomad AMR exome AF: 0.00103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000664

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000704 AC: 1027 AN: 1458252 Hom.: 16 Cov.: 29 AF XY: 0.000608 AC XY: 441 AN XY: 725364

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000584

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00736 AC: 1119 AN: 152086 Hom.: 12 Cov.: 32 AF XY: 0.00683 AC XY: 508 AN XY: 74380

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.000448 Hom.: 0

Bravo AF: 0.00876

ESP6500AA AF: 0.0275 AC: 121

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00230 AC: 279

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000549

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.74
MPC		0.74
ClinPred		0.032	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.78

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

Other links and lift over

dbSNP: rs35004667; hg19: chr8-90785005;