12-52897540-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_002273.4(KRT8):c.1340C>T(p.Ala447Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 152,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.28

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022991091).
• BP6: Variant 12-52897540-G-A is Benign according to our data. Variant chr12-52897540-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 56169.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT8	NM_002273.4	c.1340C>T	p.Ala447Val	missense_variant	8/8	ENST00000692008.1
KRT8	NM_001256282.2	c.1424C>T	p.Ala475Val	missense_variant	9/9
KRT8	NM_001256293.2	c.1340C>T	p.Ala447Val	missense_variant	9/9
KRT8	NR_045962.2	n.1791C>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT8	ENST00000692008.1	c.1340C>T	p.Ala447Val	missense_variant	8/8		NM_002273.4	P2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000192 AC: 45 AN: 234460 Hom.: 0 AF XY: 0.000195 AC XY: 25 AN XY: 128460

Gnomad AFR exome AF: 0.000202

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00160

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000827

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000531 AC: 75 AN: 1411850 Hom.: 0 Cov.: 33 AF XY: 0.0000525 AC XY: 37 AN XY: 704246

Gnomad4 AFR exome AF: 0.000274

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000608

Gnomad4 SAS exome AF: 0.0000937

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000287

Gnomad4 OTH exome AF: 0.0000508

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74484

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000181

ESP6500AA AF: 0.00120 AC: 5

ESP6500EA AF: 0.000127 AC: 1

ExAC AF: 0.000208 AC: 25

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 23, 2021

- -

Hepatitis C virus, susceptibility to Other:1

not provided, no classification provided

literature only

STRNAD Lab, University Hospital of Ulm

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	6.2
Dann	Benign	0.69
DEOGEN2	Benign	0.25	T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.023	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.40	N;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.87	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.0010	B;B;B;.
Vest4		0.25
MVP		0.71
MPC		0.50
ClinPred		0.018	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.021
gMVP		0.39

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: rs386834223; hg19: chr12-53291324; COSMIC: COSV99510092; COSMIC: COSV99510092;