Genetic Variant RIPK2:c.1029+18_1029+25delAAAAAAAA (chr8-89784141-TAAAAAAAA-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+18_1029+25delAAAAAAAA variant causes a intron change. The variant allele was found at a frequency of 0.00187 in 556,984 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0022 ( 0 hom. )

Consequence

RIPK2
NM_003821.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.92

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:

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ACMG classification

Classification was made for transcript

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

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RIPK2	NM_003821.6 link	c.1029+18_1029+25delAAAAAAAA	intron_variant	Intron 8 of 10	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1 link	c.618+18_618+25delAAAAAAAA	intron_variant	Intron 7 of 9		NP_001362289.1
RIPK2	XM_011517357.3 link	c.516+18_516+25delAAAAAAAA	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+18_1029+25delAAAAAAAA		intron_variant	Intron 8 of 10	1	NM_003821.6	ENSP00000220751.4

Frequencies

GnomAD3 genomes

AF:

0.000155

AC:

AN:

97064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000427

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00450

Gnomad NFE

AF:

0.000174

Gnomad OTH

AF:

0.000780

GnomAD4 exome

AF:

0.00223

AC:

1024

AN:

459912

Hom.:

AF XY:

0.00224

AC XY:

536

AN XY:

239288

show subpopulations

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

African (AFR)

AF:

0.00179

AC:

AN:

9510

American (AMR)

AF:

0.00291

AC:

AN:

11006

Ashkenazi Jewish (ASJ)

AF:

0.00254

AC:

AN:

10242

East Asian (EAS)

AF:

0.000145

AC:

AN:

20656

South Asian (SAS)

AF:

0.00143

AC:

AN:

25822

European-Finnish (FIN)

AF:

0.00162

AC:

AN:

28380

Middle Eastern (MID)

AF:

0.00238

AC:

AN:

1684

European-Non Finnish (NFE)

AF:

0.00245

AC:

809

AN:

330332

Other (OTH)

AF:

0.00224

AC:

AN:

22280

⚠️ 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: 0.276

Heterozygous variant carriers

100

200

301

401

501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000155

AC:

AN:

97072

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

AN XY:

44206

show subpopulations

African (AFR)

AF:

0.0000426

AC:

AN:

23468

American (AMR)

AF:

0.00

AC:

AN:

8918

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

2798

East Asian (EAS)

AF:

0.00

AC:

AN:

2856

South Asian (SAS)

AF:

0.00

AC:

AN:

2446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2610

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.000174

AC:

AN:

51758

Other (OTH)

AF:

0.000774

AC:

AN:

1292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.622

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

3.9

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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8-89784141-TAAAAAAAAAAAAAAAA-TAAAAAAAA

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