12-52515133-T-C

Variant names:

• chr12-52515133-T-C
• rs11549950
• NM_000424.4:c.1582A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:5 O:1
• Conservation: PhyloP100: -0.162
• Publications: 23 publications found

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]

KRT5 Gene-Disease associations (from GenCC):

• Dowling-Degos disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• epidermolysis bullosa simplex 1A, generalized severe

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• Dowling-Degos disease 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• epidermolysis bullosa simplex 1B, generalized intermediate

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 1C, localized

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• epidermolysis bullosa simplex 2B, generalized intermediate

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• epidermolysis bullosa simplex 2E, with migratory circinate erythema

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000303382 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	NM_000424.4	MANE Select	c.1582A>G	p.Ser528Gly	missense	Exon 9 of 9	NP_000415.2	P13647

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	ENST00000252242.9	TSL:1 MANE Select	c.1582A>G	p.Ser528Gly	missense	Exon 9 of 9	ENSP00000252242.4	P13647
	KRT5	ENST00000549511.5	TSL:2	n.789A>G		non_coding_transcript_exon	Exon 5 of 5
	KRT5	ENST00000552952.1	TSL:2	n.507A>G		non_coding_transcript_exon	Exon 2 of 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

GnomAD2 exomes AF: 0.137 AC: 32964 AN: 240242 AF XY: 0.134

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 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

African (AFR) AF: 0.258 AC: 8639 AN: 33426

American (AMR) AF: 0.158 AC: 6965 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5186 AN: 26038

East Asian (EAS) AF: 0.0246 AC: 974 AN: 39650

South Asian (SAS) AF: 0.102 AC: 8821 AN: 86074

European-Finnish (FIN) AF: 0.132 AC: 7021 AN: 53166

Middle Eastern (MID) AF: 0.191 AC: 1099 AN: 5758

European-Non Finnish (NFE) AF: 0.132 AC: 147118 AN: 1110630

Other (OTH) AF: 0.142 AC: 8545 AN: 60268

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

African (AFR) AF: 0.252 AC: 10342 AN: 41118

American (AMR) AF: 0.185 AC: 2805 AN: 15182

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3468

East Asian (EAS) AF: 0.0332 AC: 170 AN: 5128

South Asian (SAS) AF: 0.102 AC: 482 AN: 4718

European-Finnish (FIN) AF: 0.126 AC: 1317 AN: 10470

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9352 AN: 67860

Other (OTH) AF: 0.191 AC: 400 AN: 2098

Alfa AF: 0.147 Hom.: 8038

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	1	Epidermolysis bullosa simplex (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-0.16
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11549950; hg19: chr12-52908917; COSMIC: COSV52859868; COSMIC: COSV52859868;