12-52897442-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002273.4(KRT8):c.1438G>A(p.Val480Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,599,352 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (8 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.851

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036435723).
• BP6: Variant 12-52897442-C-T is Benign according to our data. Variant chr12-52897442-C-T is described in ClinVar as [Benign]. Clinvar id is 713128.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00569 (867/152254) while in subpopulation AFR AF= 0.0171 (709/41544). AF 95% confidence interval is 0.016. There are 7 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT8	NM_002273.4	c.1438G>A	p.Val480Ile	missense_variant	8/8	ENST00000692008.1
KRT8	NM_001256282.2	c.1522G>A	p.Val508Ile	missense_variant	9/9
KRT8	NM_001256293.2	c.1438G>A	p.Val480Ile	missense_variant	9/9
KRT8	NR_045962.2	n.1889G>A		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT8	ENST00000692008.1	c.1438G>A	p.Val480Ile	missense_variant	8/8		NM_002273.4	P2

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 867 AN: 152136 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

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: 0.00131

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00182 AC: 435 AN: 238674 Hom.: 5 AF XY: 0.00141 AC XY: 183 AN XY: 130050

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000825

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00133 AC: 1921 AN: 1447098 Hom.: 8 Cov.: 33 AF XY: 0.00123 AC XY: 886 AN XY: 720368

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000126

Gnomad4 NFE exome AF: 0.00105

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00569 AC: 867 AN: 152254 Hom.: 7 Cov.: 33 AF XY: 0.00513 AC XY: 382 AN XY: 74444

Gnomad4 AFR AF: 0.0171

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000828 Hom.: 0

Bravo AF: 0.00609

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0134 AC: 56

ESP6500EA AF: 0.000754 AC: 6

ExAC AF: 0.00222 AC: 268

EpiCase AF: 0.00136

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

KRT8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

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
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.66
Dann	Benign	0.90
DEOGEN2	Benign	0.20	T;T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.32	N
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.60	N;N;N;.
MutationTaster	Benign	0.91	D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.37	T;T;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.034	B;B;B;.
Vest4		0.11
MVP		0.64
MPC		0.43
ClinPred		0.0015	T
GERP RS		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs61730606; hg19: chr12-53291226;