8-89772777-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0074 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00070 ( 16 hom. )

Consequence

RIPK2
NM_003821.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.75

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

BS2

High AC in GnomAd4 at 1119 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RIPK2	NM_003821.6 link	c.802C>G	p.Leu268Val	missense_variant	Exon 6 of 11	ENST00000220751.5	NP_003812.1	O43353-1A0A0S2Z4Z8
RIPK2	NM_001375360.1 link	c.391C>G	p.Leu131Val	missense_variant	Exon 5 of 10		NP_001362289.1
RIPK2	XM_011517357.3 link	c.289C>G	p.Leu97Val	missense_variant	Exon 4 of 9		XP_011515659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RIPK2	ENST00000220751.5 link	c.802C>G	p.Leu268Val	missense_variant	Exon 6 of 11	1	NM_003821.6	ENSP00000220751.4	O43353-1
RIPK2	ENST00000522965.1 link	n.*441C>G		non_coding_transcript_exon_variant	Exon 5 of 10	1		ENSP00000429271.1	E7ERW9
RIPK2	ENST00000522965.1 link	n.*441C>G		3_prime_UTR_variant	Exon 5 of 10	1		ENSP00000429271.1	E7ERW9

Frequencies

GnomAD3 genomes

AF:

0.00736

AC:

1118

AN:

151968

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00183

AC:

456

AN:

248534

AF XY:

0.00133

show subpopulations

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 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.:

Cov.:

AF XY:

0.000608

AC XY:

441

AN XY:

725364

show subpopulations

Gnomad4 AFR exome

AF:

0.0265

AC:

882

AN:

33262

Gnomad4 AMR exome

AF:

0.00102

AC:

AN:

44210

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26006

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39570

Gnomad4 SAS exome

AF:

0.0000584

AC:

AN:

85610

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53332

Gnomad4 NFE exome

AF:

0.0000144

AC:

AN:

1110298

Gnomad4 Remaining exome

AF:

0.00126

AC:

AN:

60218

Heterozygous variant carriers

122

162

203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00736

AC:

1119

AN:

152086

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

508

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0255

AC:

0.025523

AN:

0.025523

Gnomad4 AMR

AF:

0.00210

AC:

0.00209616

AN:

0.00209616

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.000207

AC:

0.000207383

AN:

0.000207383

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000162

AC:

0.000161912

AN:

0.000161912

Gnomad4 OTH

AF:

0.00712

AC:

0.00711575

AN:

0.00711575

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000448

Hom.:

Bravo

AF:

0.00876

ESP6500AA

AF:

0.0275

AC:

121

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00230

AC:

279

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.046

Polyphen

1.0

Vest4

0.74

MVP

0.74

MPC

0.74

ClinPred

0.032

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.63

gMVP

0.78

Mutation Taster

=87/13

polymorphism

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over