Genetic Variant RIPK2:c.1029+24_1029+25delAA (chr8-89784141-TAA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003821.6(RIPK2):c.1029+24_1029+25delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0538 in 546,494 control chromosomes in the GnomAD database, including 40 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0050 ( 0 hom., cov: 0)

Exomes 𝑓: 0.064 ( 40 hom. )

Consequence

RIPK2
NM_003821.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0390

Publications

0 publications found

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:

PARAIL (HGNC:55545): (palmitic acid regulated anti-inflammatory lncRNA)

PARAIL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 485 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RIPK2	NM_003821.6 link	c.1029+24_1029+25delAA	intron_variant	Intron 8 of 10	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1 link	c.618+24_618+25delAA	intron_variant	Intron 7 of 9		NP_001362289.1
RIPK2	XM_011517357.3 link	c.516+24_516+25delAA	intron_variant	Intron 6 of 8		XP_011515659.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RIPK2	ENST00000220751.5 link	c.1029+24_1029+25delAA		intron_variant	Intron 8 of 10	1	NM_003821.6	ENSP00000220751.4

Frequencies

GnomAD3 genomes

AF:

0.00498

AC:

483

AN:

97030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00337

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.00404

Gnomad ASJ

AF:

0.00823

Gnomad EAS

AF:

0.00175

Gnomad SAS

AF:

0.00448

Gnomad FIN

AF:

0.00498

Gnomad MID

AF:

0.0135

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00391

GnomAD2 exomes

AF:

0.0371

AC:

1060

AN:

28604

AF XY:

0.0358

show subpopulations

Gnomad AFR exome

AF:

0.0813

Gnomad AMR exome

AF:

0.0615

Gnomad ASJ exome

AF:

0.0356

Gnomad EAS exome

AF:

0.128

Gnomad FIN exome

AF:

0.00838

Gnomad NFE exome

AF:

0.0213

Gnomad OTH exome

AF:

0.0517

GnomAD4 exome

AF:

0.0643

AC:

28903

AN:

449456

Hom.:

AF XY:

0.0641

AC XY:

14978

AN XY:

233696

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.108

AC:

994

AN:

9228

American (AMR)

AF:

0.0695

AC:

745

AN:

10720

Ashkenazi Jewish (ASJ)

AF:

0.0661

AC:

654

AN:

9890

East Asian (EAS)

AF:

0.128

AC:

2512

AN:

19558

South Asian (SAS)

AF:

0.0743

AC:

1869

AN:

25154

European-Finnish (FIN)

AF:

0.0480

AC:

1334

AN:

27802

Middle Eastern (MID)

AF:

0.0766

AC:

125

AN:

1632

European-Non Finnish (NFE)

AF:

0.0590

AC:

19094

AN:

323822

Other (OTH)

AF:

0.0728

AC:

1576

AN:

21650

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.323

Heterozygous variant carriers

2115

4230

6344

8459

10574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

462

924

1386

1848

2310

<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:

0.00500

AC:

485

AN:

97038

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

216

AN XY:

44192

show subpopulations

African (AFR)

AF:

0.00345

AC:

AN:

23464

American (AMR)

AF:

0.00404

AC:

AN:

8916

Ashkenazi Jewish (ASJ)

AF:

0.00823

AC:

AN:

2796

East Asian (EAS)

AF:

0.00175

AC:

AN:

2856

South Asian (SAS)

AF:

0.00450

AC:

AN:

2446

European-Finnish (FIN)

AF:

0.00498

AC:

AN:

2608

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.00559

AC:

289

AN:

51736

Other (OTH)

AF:

0.00388

AC:

AN:

1290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.039

Mutation Taster

=100/0

polymorphism

(source)

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

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8-89784141-TAAAAAAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over