Genetic Variant RIPK2:c.1029+22_1029+25delAAAA (chr8-89784141-TAAAA-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+22_1029+25delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 547,146 control chromosomes in the GnomAD database, including 100 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 0)

Exomes 𝑓: 0.12 ( 100 hom. )

Consequence

RIPK2
NM_003821.6 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.24

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 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
RIPK2	NM_003821.6 link	c.1029+22_1029+25delAAAA	intron_variant	Intron 8 of 10	ENST00000220751.5	NP_003812.1
RIPK2	NM_001375360.1 link	c.618+22_618+25delAAAA	intron_variant	Intron 7 of 9		NP_001362289.1
RIPK2	XM_011517357.3 link	c.516+22_516+25delAAAA	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+22_1029+25delAAAA		intron_variant	Intron 8 of 10	1	NM_003821.6	ENSP00000220751.4

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

AN:

97030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000853

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.000358

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000814

Gnomad FIN

AF:

0.00345

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000599

Gnomad OTH

AF:

0.000780

GnomAD2 exomes

AF:

0.0789

AC:

2258

AN:

28604

AF XY:

0.0764

show subpopulations

Gnomad AFR exome

AF:

0.0663

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.0649

Gnomad EAS exome

AF:

0.0531

Gnomad FIN exome

AF:

0.0688

Gnomad NFE exome

AF:

0.0880

Gnomad OTH exome

AF:

0.0866

GnomAD4 exome

AF:

0.125

AC:

56156

AN:

450108

Hom.:

100

AF XY:

0.123

AC XY:

28721

AN XY:

234040

show subpopulations

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

African (AFR)

AF:

0.0857

AC:

791

AN:

9230

American (AMR)

AF:

0.104

AC:

1111

AN:

10688

Ashkenazi Jewish (ASJ)

AF:

0.0968

AC:

966

AN:

9984

East Asian (EAS)

AF:

0.0473

AC:

946

AN:

19992

South Asian (SAS)

AF:

0.0845

AC:

2130

AN:

25206

European-Finnish (FIN)

AF:

0.115

AC:

3189

AN:

27678

Middle Eastern (MID)

AF:

0.122

AC:

201

AN:

1646

European-Non Finnish (NFE)

AF:

0.136

AC:

44217

AN:

324006

Other (OTH)

AF:

0.120

AC:

2605

AN:

21678

⚠️ 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: 0.371

Heterozygous variant carriers

2793

5586

8379

11172

13965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1140

2280

3420

4560

5700

<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:

0.000763

AC:

AN:

97038

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

44182

show subpopulations

African (AFR)

AF:

0.000852

AC:

AN:

23466

American (AMR)

AF:

0.00112

AC:

AN:

8918

Ashkenazi Jewish (ASJ)

AF:

0.000358

AC:

AN:

2792

East Asian (EAS)

AF:

0.00

AC:

AN:

2856

South Asian (SAS)

AF:

0.000818

AC:

AN:

2446

European-Finnish (FIN)

AF:

0.00345

AC:

AN:

2610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.000599

AC:

AN:

51732

Other (OTH)

AF:

0.000774

AC:

AN:

1292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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

1.2

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-TAAAAAAAAAAAA

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