17-40818897-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000421.5(KRT10):c.1638C>A(p.Ser546Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,145,706 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S546G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 24)

Exomes 𝑓: 0.00064 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

KRT10
NM_000421.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.645

Publications

8 publications found

Variant links:

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10 links:

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

KRT10-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003172636).

BP6

Variant 17-40818897-G-T is Benign according to our data. Variant chr17-40818897-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1191794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000421.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT10	NM_000421.5	MANE Select	c.1638C>A	p.Ser546Arg	missense	Exon 7 of 8	NP_000412.4
KRT10	NM_001379366.1		c.1638C>A	p.Ser546Arg	missense	Exon 7 of 8	NP_001366295.1	A0A1B0GVI3
KRT10-AS1	NR_160887.1		n.-248G>T		upstream_gene	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT10	ENST00000269576.6	TSL:1 MANE Select	c.1638C>A	p.Ser546Arg	missense	Exon 7 of 8	ENSP00000269576.5	P13645
KRT10	ENST00000635956.2	TSL:2	c.1638C>A	p.Ser546Arg	missense	Exon 7 of 8	ENSP00000490524.2	A0A1B0GVI3
KRT10-AS1	ENST00000301665.10	TSL:2	n.-201G>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000363

AC:

AN:

93600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000879

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000274

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000837

Gnomad SAS

AF:

0.00152

Gnomad FIN

AF:

0.000273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000164

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00876

AC:

986

AN:

112550

AF XY:

0.00897

show subpopulations

Gnomad AFR exome

AF:

0.0351

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00517

Gnomad EAS exome

AF:

0.0271

Gnomad FIN exome

AF:

0.00897

Gnomad NFE exome

AF:

0.00823

Gnomad OTH exome

AF:

0.00657

GnomAD4 exome

AF:

0.000642

AC:

735

AN:

1145706

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

439

AN XY:

564090

show subpopulations

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

African (AFR)

AF:

0.00253

AC:

AN:

19748

American (AMR)

AF:

0.00183

AC:

AN:

29528

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

19416

East Asian (EAS)

AF:

0.00283

AC:

AN:

24414

South Asian (SAS)

AF:

0.00310

AC:

161

AN:

51888

European-Finnish (FIN)

AF:

0.00118

AC:

AN:

28702

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

4090

European-Non Finnish (NFE)

AF:

0.000321

AC:

296

AN:

921732

Other (OTH)

AF:

0.000823

AC:

AN:

46188

⚠️ 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: 0.356

Heterozygous variant carriers

112

149

186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000363

AC:

AN:

93680

Hom.:

Cov.:

AF XY:

0.000262

AC XY:

AN XY:

45790

show subpopulations

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

African (AFR)

AF:

0.000876

AC:

AN:

17120

American (AMR)

AF:

0.000274

AC:

AN:

10956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2416

East Asian (EAS)

AF:

0.000840

AC:

AN:

2382

South Asian (SAS)

AF:

0.00152

AC:

AN:

2638

European-Finnish (FIN)

AF:

0.000273

AC:

AN:

7338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

184

European-Non Finnish (NFE)

AF:

0.000164

AC:

AN:

48664

Other (OTH)

AF:

0.00

AC:

AN:

1288

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 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: 0.260

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.:

ExAC

AF:

0.0134

AC:

1353

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.22

CADD

Benign

4.8

(source)

DANN

Benign

0.58

DEOGEN2

Benign

0.079

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.084

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0032

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.6

PhyloP100

-0.65

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

0.61

Vest4

0.13

MutPred

0.40

Loss of phosphorylation at S546 (P = 4e-04)

MPC

0.47

ClinPred

0.0096

GERP RS

-5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.11

gMVP

0.43

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over