12-52898743-C-T

Position:

• chr12-52898743-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002273.4(KRT8):​c.1138G>A​(p.Val380Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000751 in 1,614,206 control chromosomes in the GnomAD database, including 10 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (9 hom.)
• Consequence: KRT8 NM_002273.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 4.06

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01279372).
• BP6: Variant 12-52898743-C-T is Benign according to our data. Variant chr12-52898743-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 66524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT8	NM_002273.4	c.1138G>A	p.Val380Ile	missense_variant	6/8	ENST00000692008.1	NP_002264.1
KRT8	NM_001256282.2	c.1222G>A	p.Val408Ile	missense_variant	7/9		NP_001243211.1
KRT8	NM_001256293.2	c.1138G>A	p.Val380Ile	missense_variant	7/9		NP_001243222.1
KRT8	NR_045962.2	n.1589G>A		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT8	ENST00000692008.1	c.1138G>A	p.Val380Ile	missense_variant	6/8		NM_002273.4	ENSP00000509398	P2

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 251464 Hom.: 2 AF XY: 0.00200 AC XY: 272 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00804

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000780 AC: 1140 AN: 1461876 Hom.: 9 Cov.: 33 AF XY: 0.00102 AC XY: 741 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00738

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74482

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000393

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.00161 AC: 196

EpiCase AF: 0.000654

EpiControl AF: 0.000533

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	KRT8: BS2 -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T;.
Eigen	Benign	-0.072
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.18	.;.;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	-0.055	T
MutationAssessor	Benign	1.4	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.74	N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.033	B;B;B;.
Vest4		0.22
MVP		0.90
MPC		0.42
ClinPred		0.024	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.12
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56997521; hg19: chr12-53292527;