12-52519733-G-A

Position:

• chr12-52519733-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000424.4(KRT5):​c.555+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,611,118 control chromosomes in the GnomAD database, including 49,781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3437 hom., cov: 32)
  • Exomes 𝑓: 0.24 (46344 hom.)
• Consequence: KRT5 NM_000424.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -1.23

Genes affected

KRT5 (HGNC:6442): (keratin 5) 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 basal layer of the epidermis with family member KRT14. Mutations in these genes have been associated with a complex of diseases termed epidermolysis bullosa simplex. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-52519733-G-A is Benign according to our data. Variant chr12-52519733-G-A is described in ClinVar as [Benign]. Clinvar id is 66264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.555+9C>T		intron_variant		ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.555+9C>T		intron_variant		1	NM_000424.4	ENSP00000252242.4
KRT5	ENST00000552629.5	n.653+9C>T		intron_variant		1
KRT5	ENST00000549420.1	c.225+9C>T		intron_variant		5		ENSP00000447209.1
KRT5	ENST00000551275.1	c.*18C>T		downstream_gene_variant		4		ENSP00000448041.1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27717 AN: 151878 Hom.: 3437 Cov.: 32

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.00830

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.197 AC: 49460 AN: 251418 Hom.: 6009 AF XY: 0.203 AC XY: 27614 AN XY: 135880

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.256

Gnomad EAS exome AF: 0.00669

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.227

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.237

GnomAD4 exome AF: 0.243 AC: 353904 AN: 1459122 Hom.: 46344 Cov.: 31 AF XY: 0.241 AC XY: 175118 AN XY: 726066

Gnomad4 AFR exome AF: 0.0409

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.00363

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.231

Gnomad4 NFE exome AF: 0.270

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.182 AC: 27714 AN: 151996 Hom.: 3437 Cov.: 32 AF XY: 0.177 AC XY: 13177 AN XY: 74280

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.00832

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.200

Alfa AF: 0.248 Hom.: 6595

Bravo AF: 0.173

Asia WGS AF: 0.0820 AC: 285 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.274

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Epidermolysis bullosa simplex Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.91
CADD	Benign	0.21
DANN	Benign	0.70

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: rs638907; hg19: chr12-52913517; COSMIC: COSV52864251; COSMIC: COSV52864251;