Genetic Variant NM_015515.5:c.907A>G (chr17-40928252-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_015515.5(KRT23):c.907A>G(p.Thr303Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 1,613,648 control chromosomes in the GnomAD database, including 156,198 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.47 ( 17682 hom., cov: 31)

Exomes 𝑓: 0.43 ( 138516 hom. )

Consequence

KRT23
NM_015515.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.353

Publications

39 publications found

Variant links:

Genes affected

KRT23 (HGNC:6438): (keratin 23) The protein encoded by this gene is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. The type I cytokeratin genes are clustered in a region of chromosome 17q12-q21. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

KRT23 links:

ENSG00000234477 (HGNC:):

ENSG00000234477 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=2.0328584E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT23	NM_015515.5 link	c.907A>G	p.Thr303Ala	missense_variant	Exon 6 of 9	ENST00000209718.8	NP_056330.3	Q9C075-1A0A024R1X9Q8TC04

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT23	ENST00000209718.8 link	c.907A>G	p.Thr303Ala	missense_variant	Exon 6 of 9	1	NM_015515.5	ENSP00000209718.3		Q9C075-1

Frequencies

GnomAD3 genomes

AF:

0.473

AC:

71772

AN:

151778

Hom.:

17662

Cov.:

show subpopulations

Gnomad AFR

AF:

0.562

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.569

Gnomad ASJ

AF:

0.466

Gnomad EAS

AF:

0.712

Gnomad SAS

AF:

0.591

Gnomad FIN

AF:

0.341

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.392

Gnomad OTH

AF:

0.473

GnomAD2 exomes

AF:

0.489

AC:

122785

AN:

251344

AF XY:

0.484

show subpopulations

Gnomad AFR exome

AF:

0.563

Gnomad AMR exome

AF:

0.653

Gnomad ASJ exome

AF:

0.468

Gnomad EAS exome

AF:

0.703

Gnomad FIN exome

AF:

0.338

Gnomad NFE exome

AF:

0.399

Gnomad OTH exome

AF:

0.477

GnomAD4 exome

AF:

0.426

AC:

622154

AN:

1461752

Hom.:

138516

Cov.:

AF XY:

0.430

AC XY:

312640

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.566

AC:

18963

AN:

33476

American (AMR)

AF:

0.638

AC:

28552

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

12054

AN:

26136

East Asian (EAS)

AF:

0.729

AC:

28929

AN:

39700

South Asian (SAS)

AF:

0.579

AC:

49943

AN:

86254

European-Finnish (FIN)

AF:

0.339

AC:

18099

AN:

53410

Middle Eastern (MID)

AF:

0.577

AC:

3323

AN:

5762

European-Non Finnish (NFE)

AF:

0.392

AC:

435617

AN:

1111900

Other (OTH)

AF:

0.442

AC:

26674

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

20201

40403

60604

80806

101007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13966

27932

41898

55864

69830

<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:

0.473

AC:

71837

AN:

151896

Hom.:

17682

Cov.:

AF XY:

0.477

AC XY:

35412

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.562

AC:

23291

AN:

41420

American (AMR)

AF:

0.569

AC:

8684

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.466

AC:

1617

AN:

3468

East Asian (EAS)

AF:

0.712

AC:

3680

AN:

5170

South Asian (SAS)

AF:

0.591

AC:

2843

AN:

4812

European-Finnish (FIN)

AF:

0.341

AC:

3600

AN:

10548

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.392

AC:

26654

AN:

67914

Other (OTH)

AF:

0.469

AC:

987

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1882

3764

5645

7527

9409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

650

1300

1950

2600

3250

<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:

0.431

Hom.:

68479

Bravo

AF:

0.496

TwinsUK

AF:

0.383

AC:

1422

ALSPAC

AF:

0.387

AC:

1492

ESP6500AA

AF:

0.560

AC:

2468

ESP6500EA

AF:

0.394

AC:

3385

ExAC

AF:

0.485

AC:

58869

Asia WGS

AF:

0.617

AC:

2146

AN:

3478

EpiCase

AF:

0.412

EpiControl

AF:

0.412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.3

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.15

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.33

T;T

MetaRNN

Benign

0.0000020

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.2

N;.

PhyloP100

0.35

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.24

N;N

REVEL

Benign

0.21

Sift

Benign

0.72

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

B;.

Vest4

0.012

MPC

0.12

ClinPred

0.0025

GERP RS

-1.5

Varity_R

0.048

gMVP

0.22

Mutation Taster

=98/2

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