chr12-52518984-C-T

Position:

• chr12-52518984-C-T

Variant summary

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

The ENST00000252242.9(KRT5):​c.732G>A​(p.Leu244=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,614,044 control chromosomes in the GnomAD database, including 15,029 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1804 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13225 hom.)
• Consequence: KRT5 ENST00000252242.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 0.589

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-52518984-C-T is Benign according to our data. Variant chr12-52518984-C-T is described in ClinVar as [Benign]. Clinvar id is 66283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.589 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.732G>A	p.Leu244=	synonymous_variant	2/9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.732G>A	p.Leu244=	synonymous_variant	2/9	1	NM_000424.4	ENSP00000252242	P1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22815 AN: 152044 Hom.: 1798 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.181

GnomAD3 exomes AF: 0.132 AC: 33176 AN: 251440 Hom.: 2504 AF XY: 0.131 AC XY: 17777 AN XY: 135906

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.0302

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.131 AC: 191115 AN: 1461882 Hom.: 13225 Cov.: 33 AF XY: 0.130 AC XY: 94506 AN XY: 727244

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.0246

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.150 AC: 22847 AN: 152162 Hom.: 1804 Cov.: 32 AF XY: 0.150 AC XY: 11161 AN XY: 74388

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.178

Alfa AF: 0.118 Hom.: 414

Bravo AF: 0.154

Asia WGS AF: 0.0890 AC: 311 AN: 3478

EpiCase AF: 0.150

EpiControl AF: 0.147

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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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	-0.47
CADD	Benign	6.7
DANN	Uncertain	1.0

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: rs1132948; hg19: chr12-52912768;