chr12-52675230-T-C

Position:

chr12-52675230-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006121.4(KRT1):c.1898A>G(p.Lys633Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.306 in 1,613,660 control chromosomes in the GnomAD database, including 80,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 5697 hom., cov: 32)

Exomes 𝑓: 0.31 ( 74749 hom. )

Consequence

KRT1
NM_006121.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.673

Variant links:

Genes affected

KRT1 (HGNC:6412): (keratin 1) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the spinous and granular layers of the epidermis with family member KRT10 and mutations in these genes have been associated with bullous congenital ichthyosiform erythroderma. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.6852023E-5).

BP6

Variant 12-52675230-T-C is Benign according to our data. Variant chr12-52675230-T-C is described in ClinVar as [Benign]. Clinvar id is 309637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT1	NM_006121.4 linkuse as main transcript	c.1898A>G	p.Lys633Arg	missense_variant	9/9	ENST00000252244.3	NP_006112.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT1	ENST00000252244.3 linkuse as main transcript	c.1898A>G	p.Lys633Arg	missense_variant	9/9	1	NM_006121.4	ENSP00000252244	P1

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37248

AN:

151990

Hom.:

5701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0643

Gnomad AMI

AF:

0.139

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.312

Gnomad EAS

AF:

0.577

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.350

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.255

GnomAD3 exomes

AF:

0.309

AC:

77483

AN:

250558

Hom.:

13449

AF XY:

0.310

AC XY:

42033

AN XY:

135584

show subpopulations

Gnomad AFR exome

AF:

0.0591

Gnomad AMR exome

AF:

0.285

Gnomad ASJ exome

AF:

0.313

Gnomad EAS exome

AF:

0.590

Gnomad SAS exome

AF:

0.272

Gnomad FIN exome

AF:

0.347

Gnomad NFE exome

AF:

0.309

Gnomad OTH exome

AF:

0.321

GnomAD4 exome

AF:

0.312

AC:

456341

AN:

1461552

Hom.:

74749

Cov.:

AF XY:

0.312

AC XY:

226538

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0534

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.308

Gnomad4 EAS exome

AF:

0.595

Gnomad4 SAS exome

AF:

0.272

Gnomad4 FIN exome

AF:

0.345

Gnomad4 NFE exome

AF:

0.313

Gnomad4 OTH exome

AF:

0.313

GnomAD4 genome

AF:

0.245

AC:

37227

AN:

152108

Hom.:

5697

Cov.:

AF XY:

0.248

AC XY:

18415

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0641

Gnomad4 AMR

AF:

0.245

Gnomad4 ASJ

AF:

0.312

Gnomad4 EAS

AF:

0.577

Gnomad4 SAS

AF:

0.272

Gnomad4 FIN

AF:

0.350

Gnomad4 NFE

AF:

0.309

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.298

Hom.:

15302

Bravo

AF:

0.233

TwinsUK

AF:

0.304

AC:

1126

ALSPAC

AF:

0.300

AC:

1157

ESP6500AA

AF:

0.0681

AC:

300

ESP6500EA

AF:

0.303

AC:

2605

ExAC

AF:

0.304

AC:

36879

Asia WGS

AF:

0.360

AC:

1252

AN:

3478

EpiCase

AF:

0.302

EpiControl

AF:

0.298

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Epidermolytic ichthyosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Diffuse nonepidermolytic palmoplantar keratoderma

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.074

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.45

MetaRNN

Benign

0.000057

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.59

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Benign

0.92

Polyphen

0.33

Vest4

0.064

MPC

0.22

ClinPred

0.026

GERP RS

2.3

Varity_R

0.21

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over