Genetic Variant ENST00000552150.5:c.75T>A (chr12-52904991-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The ENST00000552150.5(KRT8):c.75T>A(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,602,140 control chromosomes in the GnomAD database, including 9,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.082 ( 715 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8549 hom. )

Consequence

KRT8
ENST00000552150.5 synonymous

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.345

Publications

7 publications found

Variant links:

Genes affected

KRT8 (HGNC:6446): (keratin 8) This gene is a member of the type II keratin family clustered on the long arm of chromosome 12. Type I and type II keratins heteropolymerize to form intermediate-sized filaments in the cytoplasm of epithelial cells. The product of this gene typically dimerizes with keratin 18 to form an intermediate filament in simple single-layered epithelial cells. This protein plays a role in maintaining cellular structural integrity and also functions in signal transduction and cellular differentiation. Mutations in this gene cause cryptogenic cirrhosis. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2012]

KRT8 Gene-Disease associations (from GenCC):

cirrhosis, familial
Inheritance: AR, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

KRT8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 12-52904991-A-T is Benign according to our data. Variant chr12-52904991-A-T is described in ClinVar as Benign. ClinVar VariationId is 3057189.Status of the report is no_assertion_criteria_provided, 0 stars.

BP7

Synonymous conserved (PhyloP=0.345 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT8	NM_002273.4 link	c.-10T>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000692008.1	NP_002264.1	P05787-1
KRT8	NM_001256282.2 link	c.75T>A	p.Pro25Pro	synonymous_variant	Exon 2 of 9		NP_001243211.1	Q7L4M3
KRT8	NR_045962.2 link	n.442T>A		non_coding_transcript_exon_variant	Exon 2 of 9
KRT8	NM_001256293.2 link	c.-10T>A		5_prime_UTR_variant	Exon 2 of 9		NP_001243222.1	P05787-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1 link	c.-10T>A		5_prime_UTR_variant	Exon 1 of 8		NM_002273.4	ENSP00000509398.1		P05787-1

Frequencies

GnomAD3 genomes

AF:

0.0826

AC:

12562

AN:

152128

Hom.:

716

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.0661

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0403

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.118

Gnomad OTH

AF:

0.0900

GnomAD2 exomes

AF:

0.0901

AC:

20783

AN:

230758

AF XY:

0.0918

show subpopulations

Gnomad AFR exome

AF:

0.0152

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.163

Gnomad EAS exome

AF:

0.000339

Gnomad FIN exome

AF:

0.152

Gnomad NFE exome

AF:

0.125

Gnomad OTH exome

AF:

0.0960

GnomAD4 exome

AF:

0.104

AC:

151461

AN:

1449894

Hom.:

8549

Cov.:

AF XY:

0.104

AC XY:

74879

AN XY:

720926

show subpopulations

African (AFR)

AF:

0.0162

AC:

541

AN:

33356

American (AMR)

AF:

0.0453

AC:

1993

AN:

43976

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

4045

AN:

26038

East Asian (EAS)

AF:

0.000430

AC:

AN:

39530

South Asian (SAS)

AF:

0.0478

AC:

4100

AN:

85788

European-Finnish (FIN)

AF:

0.150

AC:

7107

AN:

47244

Middle Eastern (MID)

AF:

0.0790

AC:

451

AN:

5712

European-Non Finnish (NFE)

AF:

0.115

AC:

127641

AN:

1108152

Other (OTH)

AF:

0.0926

AC:

5566

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

7769

15538

23306

31075

38844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4432

8864

13296

17728

22160

<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:

0.0825

AC:

12558

AN:

152246

Hom.:

715

Cov.:

AF XY:

0.0817

AC XY:

6079

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0193

AC:

804

AN:

41554

American (AMR)

AF:

0.0661

AC:

1011

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

563

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5166

South Asian (SAS)

AF:

0.0406

AC:

196

AN:

4830

European-Finnish (FIN)

AF:

0.150

AC:

1591

AN:

10616

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.118

AC:

8037

AN:

67992

Other (OTH)

AF:

0.0890

AC:

188

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

587

1174

1760

2347

2934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.106

Hom.:

182

Bravo

AF:

0.0730

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KRT8-related disorder

Benign:1

Nov 12, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.34

PromoterAI

-0.0080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over