NM_002273.4:c.681A>G

Variant names:

• chr12-52900597-T-C
• rs8608
• NM_002273.4:c.681A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_002273.4(KRT8):​c.681A>G​(p.Leu227Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,603,098 control chromosomes in the GnomAD database, including 226,251 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.50 (19461 hom., cov: 31)
  • Exomes 𝑓: 0.53 (206790 hom.)
• Consequence: KRT8 NM_002273.4 synonymous
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.172
• Publications: 23 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: AR, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=0.172 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT8	NM_002273.4	MANE Select	c.681A>G	p.Leu227Leu	synonymous	Exon 4 of 8	NP_002264.1
	KRT8	NM_001256282.2		c.765A>G	p.Leu255Leu	synonymous	Exon 5 of 9	NP_001243211.1
	KRT8	NM_001256293.2		c.681A>G	p.Leu227Leu	synonymous	Exon 5 of 9	NP_001243222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT8	ENST00000692008.1	MANE Select	c.681A>G	p.Leu227Leu	synonymous	Exon 4 of 8	ENSP00000509398.1
	KRT8	ENST00000552150.5	TSL:1	c.765A>G	p.Leu255Leu	synonymous	Exon 5 of 9	ENSP00000449404.1
	KRT8	ENST00000293308.11	TSL:5	c.681A>G	p.Leu227Leu	synonymous	Exon 5 of 9	ENSP00000293308.6

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76209 AN: 151788 Hom.: 19423 Cov.: 31

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.728

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.507

GnomAD2 exomes AF: 0.555 AC: 139593 AN: 251298 AF XY: 0.558

Gnomad AFR exome AF: 0.441

Gnomad AMR exome AF: 0.697

Gnomad ASJ exome AF: 0.486

Gnomad EAS exome AF: 0.625

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.511

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.529 AC: 767811 AN: 1451192 Hom.: 206790 Cov.: 30 AF XY: 0.533 AC XY: 385205 AN XY: 722404

African (AFR) AF: 0.446 AC: 14811 AN: 33238

American (AMR) AF: 0.681 AC: 30425 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12902 AN: 26072

East Asian (EAS) AF: 0.636 AC: 25203 AN: 39652

South Asian (SAS) AF: 0.698 AC: 60057 AN: 86006

European-Finnish (FIN) AF: 0.425 AC: 22650 AN: 53324

Middle Eastern (MID) AF: 0.560 AC: 2676 AN: 4778

European-Non Finnish (NFE) AF: 0.514 AC: 567282 AN: 1103442

Other (OTH) AF: 0.530 AC: 31805 AN: 59982

GnomAD4 genome AF: 0.502 AC: 76295 AN: 151906 Hom.: 19461 Cov.: 31 AF XY: 0.505 AC XY: 37510 AN XY: 74226

African (AFR) AF: 0.443 AC: 18356 AN: 41420

American (AMR) AF: 0.573 AC: 8749 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1752 AN: 3472

East Asian (EAS) AF: 0.624 AC: 3207 AN: 5140

South Asian (SAS) AF: 0.729 AC: 3510 AN: 4812

European-Finnish (FIN) AF: 0.413 AC: 4363 AN: 10556

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34551 AN: 67928

Other (OTH) AF: 0.510 AC: 1077 AN: 2112

Alfa AF: 0.513 Hom.: 20110

Bravo AF: 0.513

Asia WGS AF: 0.612 AC: 2128 AN: 3478

EpiCase AF: 0.523

EpiControl AF: 0.523

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.8
DANN	Benign	0.62
PhyloP100		0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	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: rs8608; hg19: chr12-53294381; COSMIC: COSV53177077; COSMIC: COSV53177077;