12-52514757-C-T

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.*185G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 617,116 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (90 hom., cov: 31)
  • Exomes 𝑓: 0.011 (104 hom.)
• Consequence: KRT5 NM_000424.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31

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=-0.91).
• BP6: Variant 12-52514757-C-T is Benign according to our data. Variant chr12-52514757-C-T is described in ClinVar as [Benign]. Clinvar id is 309551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT5	NM_000424.4	c.*185G>A		3_prime_UTR_variant	9/9	ENST00000252242.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT5	ENST00000252242.9	c.*185G>A		3_prime_UTR_variant	9/9	1	NM_000424.4	P1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3477 AN: 151958 Hom.: 89 Cov.: 31

Gnomad AFR AF: 0.0510

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.000567

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.0278

GnomAD4 exome AF: 0.0106 AC: 4914 AN: 465040 Hom.: 104 Cov.: 5 AF XY: 0.0102 AC XY: 2490 AN XY: 244986

Gnomad4 AFR exome AF: 0.0534

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.000502

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.000357

Gnomad4 NFE exome AF: 0.00491

Gnomad4 OTH exome AF: 0.0147

GnomAD4 genome AF: 0.0230 AC: 3499 AN: 152076 Hom.: 90 Cov.: 31 AF XY: 0.0238 AC XY: 1770 AN XY: 74364

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.0502

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.0300

Gnomad4 SAS AF: 0.0131

Gnomad4 FIN AF: 0.000567

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.0277

Asia WGS AF: 0.0280 AC: 97 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	-0.91
Cadd	Benign	0.92
Dann	Benign	0.41

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: rs11549960; hg19: chr12-52908541;