rs57749775

Variant names:

• chr12-52904822-A-G
• rs57749775
• NM_002273.4:c.160T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-52904822-A-G
• chr12-52904822-A-C
• chr12-52904822-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002273.4(KRT8):​c.160T>C​(p.Tyr54His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,612,398 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y54C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (9 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2 O:2
• Conservation: PhyloP100: 0.392
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06538835).
• BP6: Variant 12-52904822-A-G is Benign according to our data. Variant chr12-52904822-A-G is described in ClinVar as Benign. ClinVar VariationId is 14631.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 = 0.00658 (1001/152232) while in subpopulation AFR AF = 0.023 (954/41550). AF 95% confidence interval is 0.0218. There are 10 homozygotes in GnomAd4. There are 471 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,Unknown gene

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.160T>C	p.Tyr54His	missense	Exon 1 of 8	NP_002264.1	P05787-1
	KRT8	NM_001256282.2		c.244T>C	p.Tyr82His	missense	Exon 2 of 9	NP_001243211.1	P05787-2
	KRT8	NM_001256293.2		c.160T>C	p.Tyr54His	missense	Exon 2 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.160T>C	p.Tyr54His	missense	Exon 1 of 8	ENSP00000509398.1	P05787-1
	KRT8	ENST00000552150.5	TSL:1	c.244T>C	p.Tyr82His	missense	Exon 2 of 9	ENSP00000449404.1	P05787-2
	KRT8	ENST00000871797.1		c.160T>C	p.Tyr54His	missense	Exon 1 of 8	ENSP00000541856.1

Frequencies

GnomAD3 genomes AF: 0.00658 AC: 1001 AN: 152114 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00170 AC: 421 AN: 248332 AF XY: 0.00136

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000805

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000655 AC: 956 AN: 1460166 Hom.: 9 Cov.: 32 AF XY: 0.000613 AC XY: 445 AN XY: 726402

African (AFR) AF: 0.0219 AC: 732 AN: 33438

American (AMR) AF: 0.00190 AC: 85 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52730

Middle Eastern (MID) AF: 0.00119 AC: 6 AN: 5030

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111942

Other (OTH) AF: 0.00149 AC: 90 AN: 60298

GnomAD4 genome AF: 0.00658 AC: 1001 AN: 152232 Hom.: 10 Cov.: 32 AF XY: 0.00633 AC XY: 471 AN XY: 74434

African (AFR) AF: 0.0230 AC: 954 AN: 41550

American (AMR) AF: 0.00222 AC: 34 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00219 Hom.: 2

Bravo AF: 0.00717

ESP6500AA AF: 0.0147 AC: 64

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.00199 AC: 241

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cirrhosis, cryptogenic (2)
-	-	1	Hepatitis C virus, susceptibility to (1)
-	-	1	not specified (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.046	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.39
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.34
Sift	Benign	0.045	D
Sift4G	Benign	0.063	T
Polyphen		0.0070	B
Vest4		0.74
MVP		0.87
MPC		0.73
ClinPred		0.043	T
GERP RS		2.1
PromoterAI		0.22	Neutral
Varity_R		0.17
gMVP		0.56
Mutation Taster		=94/6	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: rs57749775; hg19: chr12-53298606;