Genetic Variant AKR1C8:p.Cys209Phe (chr10-5158663-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001395972.1(AKR1C8):c.626G>T(p.Cys209Phe) variant causes a missense change. The variant allele was found at a frequency of 0.283 in 489,726 control chromosomes in the GnomAD database, including 22,572 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 0.28 ( 6762 hom., cov: 32)

Exomes 𝑓: 0.28 ( 15810 hom. )

Consequence

AKR1C8
NM_001395972.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.64

Publications

5 publications found

Variant links:

Genes affected

AKR1C8 (HGNC:23469): (aldo-keto reductase family 1 member C8) Predicted to enable D-threo-aldose 1-dehydrogenase activity; aldo-keto reductase (NADP) activity; and estradiol 17-beta-dehydrogenase activity. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

AKR1C8 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 (MetaRNN=0.0050997436).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.357 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C8	NM_001395972.1 link	c.626G>T	p.Cys209Phe	missense_variant	Exon 6 of 9	ENST00000648824.2	NP_001382901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AKR1C8	ENST00000648824.2 link	c.626G>T	p.Cys209Phe	missense_variant	Exon 6 of 9		NM_001395972.1	ENSP00000496804.1	A0A3B3IRI8
AKR1C8	ENST00000584929.7 link	n.*292G>T		non_coding_transcript_exon_variant	Exon 7 of 10	6		ENSP00000496857.1	Q5T2L2
AKR1C8	ENST00000584929.7 link	n.*292G>T		3_prime_UTR_variant	Exon 7 of 10	6		ENSP00000496857.1	Q5T2L2
AKR1C8	ENST00000578467.2 link	n.719-863G>T		intron_variant	Intron 6 of 7	2

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42375

AN:

151910

Hom.:

6762

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.347

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.239

Gnomad EAS

AF:

0.00328

Gnomad SAS

AF:

0.182

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.361

Gnomad OTH

AF:

0.246

GnomAD2 exomes

AF:

0.249

AC:

44693

AN:

179672

AF XY:

0.249

show subpopulations

Gnomad AFR exome

AF:

0.154

Gnomad AMR exome

AF:

0.151

Gnomad ASJ exome

AF:

0.235

Gnomad EAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.404

Gnomad NFE exome

AF:

0.332

Gnomad OTH exome

AF:

0.275

GnomAD4 exome

AF:

0.285

AC:

96184

AN:

337700

Hom.:

15810

Cov.:

AF XY:

0.279

AC XY:

53118

AN XY:

190712

show subpopulations

African (AFR)

AF:

0.171

AC:

1589

AN:

9284

American (AMR)

AF:

0.152

AC:

4706

AN:

31004

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

2626

AN:

11096

East Asian (EAS)

AF:

0.00167

AC:

AN:

11374

South Asian (SAS)

AF:

0.194

AC:

12002

AN:

61834

European-Finnish (FIN)

AF:

0.400

AC:

11617

AN:

29018

Middle Eastern (MID)

AF:

0.157

AC:

397

AN:

2524

European-Non Finnish (NFE)

AF:

0.354

AC:

58927

AN:

166528

Other (OTH)

AF:

0.286

AC:

4301

AN:

15038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

3261

6522

9782

13043

16304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

240

480

720

960

1200

<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:

0.279

AC:

42388

AN:

152026

Hom.:

6762

Cov.:

AF XY:

0.279

AC XY:

20698

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.176

AC:

7284

AN:

41470

American (AMR)

AF:

0.242

AC:

3696

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

828

AN:

3470

East Asian (EAS)

AF:

0.00328

AC:

AN:

5178

South Asian (SAS)

AF:

0.183

AC:

881

AN:

4814

European-Finnish (FIN)

AF:

0.404

AC:

4260

AN:

10548

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.361

AC:

24541

AN:

67960

Other (OTH)

AF:

0.243

AC:

513

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1468

2935

4403

5870

7338

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

432

864

1296

1728

2160

<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:

0.312

Hom.:

5128

Bravo

AF:

0.261

TwinsUK

AF:

0.358

AC:

1329

ALSPAC

AF:

0.371

AC:

1431

ExAC

AF:

0.165

AC:

18788

Asia WGS

AF:

0.0980

AC:

340

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.99

PhyloP100

4.6

GERP RS

3.7

gMVP

0.77

Splicing

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