Genetic Variant RIPK2:c.1029+22_1029+25dupAAAA (chr8-89784141-T-TAAAA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000220751.5(RIPK2):c.1029+2_1029+3insAAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.020 ( 47 hom., cov: 0)

Exomes 𝑓: 0.00078 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RIPK2
ENST00000220751.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.604

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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000220751.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RIPK2	NM_003821.6	MANE Select	c.1029+22_1029+25dupAAAA		intron	N/A	NP_003812.1
	RIPK2	NM_001375360.1		c.618+22_618+25dupAAAA		intron	N/A	NP_001362289.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
RIPK2	ENST00000220751.5	TSL:1 MANE Select	c.1029+2_1029+3insAAAA	splice_region intron	N/A	ENSP00000220751.4
RIPK2	ENST00000522965.1	TSL:1	n.668+2_668+3insAAAA	splice_region intron	N/A	ENSP00000429271.1
RIPK2	ENST00000929530.1		c.1089+2_1089+3insAAAA	splice_region intron	N/A	ENSP00000599589.1

Frequencies

GnomAD3 genomes

AF:

0.0203

AC:

1968

AN:

97002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0694

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.00572

Gnomad EAS

AF:

0.0448

Gnomad SAS

AF:

0.00854

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00901

Gnomad NFE

AF:

0.000792

Gnomad OTH

AF:

0.0218

GnomAD4 exome

AF:

0.000783

AC:

361

AN:

460938

Hom.:

Cov.:

AF XY:

0.000834

AC XY:

200

AN XY:

239884

show subpopulations

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

African (AFR)

AF:

0.00614

AC:

AN:

9448

American (AMR)

AF:

0.00199

AC:

AN:

11034

Ashkenazi Jewish (ASJ)

AF:

0.000877

AC:

AN:

10268

East Asian (EAS)

AF:

0.00467

AC:

AN:

20540

South Asian (SAS)

AF:

0.00274

AC:

AN:

25874

European-Finnish (FIN)

AF:

0.0000702

AC:

AN:

28494

Middle Eastern (MID)

AF:

0.000595

AC:

AN:

1682

European-Non Finnish (NFE)

AF:

0.000217

AC:

AN:

331268

Other (OTH)

AF:

0.00134

AC:

AN:

22330

⚠️ 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: 0.342

Heterozygous variant carriers

112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0203

AC:

1974

AN:

97010

Hom.:

Cov.:

AF XY:

0.0213

AC XY:

939

AN XY:

44186

show subpopulations

African (AFR)

AF:

0.0695

AC:

1628

AN:

23426

American (AMR)

AF:

0.0122

AC:

109

AN:

8906

Ashkenazi Jewish (ASJ)

AF:

0.00572

AC:

AN:

2796

East Asian (EAS)

AF:

0.0448

AC:

128

AN:

2854

South Asian (SAS)

AF:

0.00859

AC:

AN:

2446

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2610

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.000792

AC:

AN:

51754

Other (OTH)

AF:

0.0224

AC:

AN:

1292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

166

248

331

414

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.60

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-TAAAAAAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over