rs2232562

Positions:

• chr12-52645289-G-A
• chr12-52645289-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000423.3(KRT2):​c.1650C>T​(p.Gly550=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,613,806 control chromosomes in the GnomAD database, including 256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (127 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (129 hom.)
• Consequence: KRT2 NM_000423.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.02

Genes affected

KRT2 (HGNC:6439): (keratin 2) 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 expressed largely in the upper spinous layer of epidermal keratinocytes and mutations in this gene 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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-52645289-G-A is Benign according to our data. Variant chr12-52645289-G-A is described in ClinVar as [Benign]. Clinvar id is 309598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT2	NM_000423.3	c.1650C>T	p.Gly550=	synonymous_variant	9/9	ENST00000309680.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT2	ENST00000309680.4	c.1650C>T	p.Gly550=	synonymous_variant	9/9	1	NM_000423.3	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3315 AN: 151832 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.0705

Gnomad AMR AF: 0.00807

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00593 AC: 1490 AN: 251182 Hom.: 54 AF XY: 0.00418 AC XY: 568 AN XY: 135740

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.00390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000502

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00269 AC: 3927 AN: 1461856 Hom.: 129 Cov.: 32 AF XY: 0.00232 AC XY: 1689 AN XY: 727238

Gnomad4 AFR exome AF: 0.0820

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00662

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.0219 AC: 3324 AN: 151950 Hom.: 127 Cov.: 32 AF XY: 0.0218 AC XY: 1619 AN XY: 74272

Gnomad4 AFR AF: 0.0737

Gnomad4 AMR AF: 0.00806

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00232

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00600 Hom.: 36

Bravo AF: 0.0255

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

KRT2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ichthyosis bullosa of Siemens 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.70
DANN	Benign	0.39

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

Other links and lift over

dbSNP: rs2232562; hg19: chr12-53039073; COSMIC: COSV59009070; COSMIC: COSV59009070;