12-52897546-G-A

Variant names:

• chr12-52897546-G-A
• rs748771942
• NM_002273.4:c.1334C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002273.4(KRT8):​c.1334C>T​(p.Ser445Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000044 in 1,591,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S445C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14961493).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002273.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT8	NM_002273.4	MANE Select	c.1334C>T	p.Ser445Phe	missense	Exon 8 of 8	NP_002264.1	P05787-1
	KRT8	NM_001256282.2		c.1418C>T	p.Ser473Phe	missense	Exon 9 of 9	NP_001243211.1	P05787-2
	KRT8	NM_001256293.2		c.1334C>T	p.Ser445Phe	missense	Exon 9 of 9	NP_001243222.1	P05787-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT8	ENST00000692008.1	MANE Select	c.1334C>T	p.Ser445Phe	missense	Exon 8 of 8	ENSP00000509398.1	P05787-1
	KRT8	ENST00000552150.5	TSL:1	c.1418C>T	p.Ser473Phe	missense	Exon 9 of 9	ENSP00000449404.1	P05787-2
	KRT8	ENST00000871797.1		c.1340C>T	p.Ser447Phe	missense	Exon 8 of 8	ENSP00000541856.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000128 AC: 3 AN: 234420 AF XY: 0.0000156

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1439474 Hom.: 0 Cov.: 33 AF XY: 0.00000419 AC XY: 3 AN XY: 716822

African (AFR) AF: 0.0000901 AC: 3 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4514

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106026

Other (OTH) AF: 0.00 AC: 0 AN: 59932

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74372

African (AFR) AF: 0.0000965 AC: 4 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000166 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Uncertain	0.97
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.28
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.0070	B
Vest4		0.28
MutPred		0.28		Loss of glycosylation at S445 (P = 0.0013)
MVP		0.80
MPC		0.56
ClinPred		0.14	T
GERP RS		4.5
Varity_R		0.10
gMVP		0.50
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs748771942; hg19: chr12-53291330;