chr12-52519175-G-A

Position:

• chr12-52519175-G-A

Variant summary

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

The ENST00000252242.9(KRT5):​c.556-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,613,858 control chromosomes in the GnomAD database, including 15,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2135 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13563 hom.)
• Consequence: KRT5 ENST00000252242.9 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.384

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-52519175-G-A is Benign according to our data. Variant chr12-52519175-G-A is described in ClinVar as [Benign]. Clinvar id is 256044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.556-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.556-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000424.4	ENSP00000252242	P1
KRT5	ENST00000552629.5	n.654-15C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		1
KRT5	ENST00000549420.1	c.226-15C>T		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000447209
KRT5	ENST00000551013.1	n.84-15C>T		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24453 AN: 152048 Hom.: 2128 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.135 AC: 33891 AN: 251080 Hom.: 2621 AF XY: 0.133 AC XY: 18052 AN XY: 135722

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0303

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.132 AC: 193020 AN: 1461692 Hom.: 13563 Cov.: 37 AF XY: 0.131 AC XY: 95309 AN XY: 727158

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0247

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.161 AC: 24491 AN: 152166 Hom.: 2135 Cov.: 32 AF XY: 0.161 AC XY: 11970 AN XY: 74394

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.181

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.0333

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.185

Alfa AF: 0.0981 Hom.: 189

Bravo AF: 0.166

Asia WGS AF: 0.0910 AC: 318 AN: 3478

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	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
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	-0.80
CADD	Benign	3.4
DANN	Benign	0.69

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: rs60314569; hg19: chr12-52912959;