rs11549950

chr12-52515133-T-C

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.1582A>G(p.Ser528Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 1,610,452 control chromosomes in the GnomAD database, including 16,355 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2470 hom., cov: 30)
  • Exomes 𝑓: 0.13 (13885 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.162

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 (MetaRNN=0.004264325).
• BP6: Variant 12-52515133-T-C is Benign according to our data. Variant chr12-52515133-T-C is described in ClinVar as [Benign]. Clinvar id is 66223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT5	NM_000424.4	c.1582A>G	p.Ser528Gly	missense_variant	9/9	ENST00000252242.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT5	ENST00000252242.9	c.1582A>G	p.Ser528Gly	missense_variant	9/9	1	NM_000424.4	P1
KRT5	ENST00000549511.5	n.789A>G		non_coding_transcript_exon_variant	5/5	2
KRT5	ENST00000552952.1	n.507A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25823 AN: 151124 Hom.: 2461 Cov.: 30

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.137 AC: 32964 AN: 240242 Hom.: 2585 AF XY: 0.134 AC XY: 17477 AN XY: 130312

Gnomad AFR exome AF: 0.259

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0299

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.133 AC: 194368 AN: 1459208 Hom.: 13885 Cov.: 36 AF XY: 0.132 AC XY: 95822 AN XY: 725718

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0246

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.132

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.142

GnomAD4 genome AF: 0.171 AC: 25862 AN: 151244 Hom.: 2470 Cov.: 30 AF XY: 0.170 AC XY: 12586 AN XY: 73852

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.0332

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.191

Alfa AF: 0.145 Hom.: 4327

Bravo AF: 0.178

TwinsUK AF: 0.131 AC: 486

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.238 AC: 1049

ESP6500EA AF: 0.140 AC: 1202

ExAC AF: 0.133 AC: 16085

Asia WGS AF: 0.0950 AC: 331 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.18
Dann	Benign	0.33
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.43	N
REVEL	Benign	0.22
Sift	Benign	0.47	T
Sift4G	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.060
MPC		0.20
ClinPred		0.0037	T
GERP RS		0.084
Varity_R		0.033
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs11549950; hg19: chr12-52908917; COSMIC: COSV52859868; COSMIC: COSV52859868;