Genetic Variant RPS6KA2:c.1938+19G>A (chr6-166418206-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021135.6(RPS6KA2):c.1938+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,494,118 control chromosomes in the GnomAD database, including 130,826 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 9140 hom., cov: 32)

Exomes 𝑓: 0.42 ( 121686 hom. )

Consequence

RPS6KA2
NM_021135.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.98

Publications

13 publications found

Variant links:

Genes affected

RPS6KA2 (HGNC:10431): (ribosomal protein S6 kinase A2) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains two non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Alternative splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jan 2016]

RPS6KA2 links:

LOC124901460 (HGNC:):

LOC124901460 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA2	NM_021135.6 link	c.1938+19G>A		intron_variant	Intron 19 of 20	ENST00000265678.9	NP_066958.2	Q15349-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA2	ENST00000265678.9 link	c.1938+19G>A		intron_variant	Intron 19 of 20	1	NM_021135.6	ENSP00000265678.4		Q15349-1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47073

AN:

151912

Hom.:

9139

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0786

Gnomad AMI

AF:

0.345

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.418

Gnomad EAS

AF:

0.213

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.342

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.443

Gnomad OTH

AF:

0.351

GnomAD2 exomes

AF:

0.358

AC:

85969

AN:

240178

AF XY:

0.374

show subpopulations

Gnomad AFR exome

AF:

0.0701

Gnomad AMR exome

AF:

0.208

Gnomad ASJ exome

AF:

0.434

Gnomad EAS exome

AF:

0.200

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.441

Gnomad OTH exome

AF:

0.401

GnomAD4 exome

AF:

0.418

AC:

560390

AN:

1342088

Hom.:

121686

Cov.:

AF XY:

0.420

AC XY:

283029

AN XY:

673444

show subpopulations

African (AFR)

AF:

0.0668

AC:

2045

AN:

30604

American (AMR)

AF:

0.218

AC:

8790

AN:

40248

Ashkenazi Jewish (ASJ)

AF:

0.426

AC:

10689

AN:

25064

East Asian (EAS)

AF:

0.217

AC:

8492

AN:

39116

South Asian (SAS)

AF:

0.433

AC:

35310

AN:

81586

European-Finnish (FIN)

AF:

0.356

AC:

18993

AN:

53304

Middle Eastern (MID)

AF:

0.417

AC:

2302

AN:

5518

European-Non Finnish (NFE)

AF:

0.446

AC:

450939

AN:

1010306

Other (OTH)

AF:

0.405

AC:

22830

AN:

56342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

15254

30508

45761

61015

76269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12864

25728

38592

51456

64320

<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:

0.310

AC:

47061

AN:

152030

Hom.:

9140

Cov.:

AF XY:

0.305

AC XY:

22671

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0783

AC:

3247

AN:

41480

American (AMR)

AF:

0.282

AC:

4301

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.418

AC:

1451

AN:

3468

East Asian (EAS)

AF:

0.213

AC:

1104

AN:

5180

South Asian (SAS)

AF:

0.424

AC:

2042

AN:

4820

European-Finnish (FIN)

AF:

0.342

AC:

3607

AN:

10544

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.443

AC:

30130

AN:

67956

Other (OTH)

AF:

0.352

AC:

745

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1510

3020

4529

6039

7549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.398

Hom.:

23889

Bravo

AF:

0.294

Asia WGS

AF:

0.303

AC:

1053

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.017

(source)

DANN

Benign

0.39

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism (auto)

(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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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