Genetic Variant NM_001353.6:c.549G>A (chr10-4968923-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The NM_001353.6(AKR1C1):c.549G>A(p.Lys183Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,614,164 control chromosomes in the GnomAD database, including 49 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 0.010 ( 31 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 18 hom. )

Consequence

AKR1C1
NM_001353.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.516

Publications

1 publications found

Variant links:

Genes affected

AKR1C1 (HGNC:384): (aldo-keto reductase family 1 member C1) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the reaction of progesterone to the inactive form 20-alpha-hydroxy-progesterone. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]

AKR1C1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.129).

BP7

Synonymous conserved (PhyloP=0.516 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00999 (1521/152276) while in subpopulation AFR AF = 0.0348 (1445/41566). AF 95% confidence interval is 0.0333. There are 31 homozygotes in GnomAd4. There are 710 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C1	NM_001353.6 link	c.549G>A	p.Lys183Lys	synonymous_variant	Exon 5 of 9	ENST00000380872.9	NP_001344.2	Q04828

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AKR1C1	ENST00000380872.9 link	c.549G>A	p.Lys183Lys	synonymous_variant	Exon 5 of 9	1	NM_001353.6	ENSP00000370254.4	Q04828
AKR1C1	ENST00000442997.5 link	c.447G>A	p.Lys149Lys	synonymous_variant	Exon 5 of 7	3		ENSP00000416415.1	H0Y804
AKR1C1	ENST00000380859.1 link	c.555G>A	p.Lys185Lys	synonymous_variant	Exon 5 of 6	3		ENSP00000370240.1	A6NHU4
AKR1C1	ENST00000477661.1 link	n.2006G>A		non_coding_transcript_exon_variant	Exon 4 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.0100

AC:

1521

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0349

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00256

AC:

645

AN:

251476

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.0355

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00102

AC:

1496

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000884

AC XY:

643

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0372

AC:

1247

AN:

33480

American (AMR)

AF:

0.00168

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000174

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1112006

Other (OTH)

AF:

0.00220

AC:

133

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00999

AC:

1521

AN:

152276

Hom.:

Cov.:

AF XY:

0.00953

AC XY:

710

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0348

AC:

1445

AN:

41566

American (AMR)

AF:

0.00360

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68018

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00252

Hom.:

Bravo

AF:

0.0117

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.1

(source)

DANN

Benign

0.45

PhyloP100

0.52

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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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