12-52514689-G-A

Position:

• chr12-52514689-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000424.4(KRT5):​c.*253C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 490,176 control chromosomes in the GnomAD database, including 4,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.15 (1797 hom., cov: 32)
  • Exomes 𝑓: 0.12 (2956 hom.)
• Consequence: KRT5 NM_000424.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.171

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-52514689-G-A is Benign according to our data. Variant chr12-52514689-G-A is described in ClinVar as [Benign]. Clinvar id is 309550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT5	NM_000424.4	c.*253C>T		3_prime_UTR_variant	9/9	ENST00000252242.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT5	ENST00000252242.9	c.*253C>T		3_prime_UTR_variant	9/9	1	NM_000424.4	P1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22811 AN: 151990 Hom.: 1791 Cov.: 32

Gnomad AFR AF: 0.179

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0337

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.122 AC: 41236 AN: 338068 Hom.: 2956 Cov.: 2 AF XY: 0.120 AC XY: 20796 AN XY: 173386

Gnomad4 AFR exome AF: 0.173

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.0208

Gnomad4 SAS exome AF: 0.0796

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.150 AC: 22842 AN: 152108 Hom.: 1797 Cov.: 32 AF XY: 0.150 AC XY: 11155 AN XY: 74378

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.0333

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.178

Alfa AF: 0.143 Hom.: 1292

Bravo AF: 0.154

Asia WGS AF: 0.0900 AC: 314 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermolysis bullosa simplex 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	-0.86
CADD	Benign	1.6
DANN	Benign	0.67

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: rs6603; hg19: chr12-52908473;