Genetic Variant KRT8:c.324+1122C>T (chr12-52903536-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_001256282.2(KRT8):c.408+1122C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 152,102 control chromosomes in the GnomAD database, including 10,515 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 0.37 ( 10514 hom., cov: 32)

Exomes 𝑓: 0.39 ( 1 hom. )

Consequence

KRT8
NM_001256282.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.17

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256282.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KRT8	NM_002273.4	MANE Select	c.324+1122C>T	intron	N/A	NP_002264.1
KRT8	NM_001256282.2		c.408+1122C>T	intron	N/A	NP_001243211.1
KRT8	NM_001256293.2		c.324+1122C>T	intron	N/A	NP_001243222.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KRT8	ENST00000692008.1	MANE Select	c.324+1122C>T	intron	N/A	ENSP00000509398.1
KRT8	ENST00000552150.5	TSL:1	c.408+1122C>T	intron	N/A	ENSP00000449404.1
KRT8	ENST00000546900.1	TSL:3	c.-72C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000450340.1

Frequencies

GnomAD3 genomes

AF:

0.366

AC:

55567

AN:

151956

Hom.:

10489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.382

Gnomad AMI

AF:

0.525

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.324

Gnomad EAS

AF:

0.137

Gnomad SAS

AF:

0.321

Gnomad FIN

AF:

0.276

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.406

Gnomad OTH

AF:

0.356

GnomAD4 exome

AF:

0.393

AC:

AN:

Hom.:

Cov.:

AF XY:

0.444

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.333

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.400

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.366

AC:

55637

AN:

152074

Hom.:

10514

Cov.:

AF XY:

0.358

AC XY:

26583

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.382

AC:

15847

AN:

41512

American (AMR)

AF:

0.299

AC:

4571

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.324

AC:

1125

AN:

3472

East Asian (EAS)

AF:

0.137

AC:

706

AN:

5148

South Asian (SAS)

AF:

0.322

AC:

1552

AN:

4822

European-Finnish (FIN)

AF:

0.276

AC:

2929

AN:

10596

Middle Eastern (MID)

AF:

0.414

AC:

121

AN:

292

European-Non Finnish (NFE)

AF:

0.406

AC:

27554

AN:

67918

Other (OTH)

AF:

0.357

AC:

754

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1814

3629

5443

7258

9072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<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:

0.391

Hom.:

27948

Bravo

AF:

0.369

Asia WGS

AF:

0.231

AC:

802

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

2.2

PromoterAI

-0.044

Neutral

(source)

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over