chr12-52519884-C-T

Variant names:

• chr12-52519884-C-T
• rs11170164
• NM_000424.4:c.413G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000424.4(KRT5):​c.413G>A​(p.Gly138Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0691 in 1,613,822 control chromosomes in the GnomAD database, including 4,399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G138V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.052 (300 hom., cov: 31)
  • Exomes 𝑓: 0.071 (4099 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 5.33
• Publications: 62 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: Orphanet, G2P
• epidermolysis bullosa simplex 1A, generalized severe

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

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

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

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

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

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000424.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0046600103).
• BP6: Variant 12-52519884-C-T is Benign according to our data. Variant chr12-52519884-C-T is described in ClinVar as Benign. ClinVar VariationId is 66234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0791 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.413G>A	p.Gly138Glu	missense	Exon 1 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.413G>A	p.Gly138Glu	missense	Exon 1 of 9	ENSP00000252242.4	P13647
	KRT5	ENST00000552629.5	TSL:1	n.511G>A		non_coding_transcript_exon	Exon 1 of 7
	KRT5	ENST00000549420.1	TSL:5	c.83G>A	p.Gly28Glu	missense	Exon 2 of 5	ENSP00000447209.1	F8W0C6

Frequencies

GnomAD3 genomes AF: 0.0523 AC: 7939 AN: 151822 Hom.: 299 Cov.: 31

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0471

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.0533

Gnomad FIN AF: 0.0898

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0809

Gnomad OTH AF: 0.0431

GnomAD2 exomes AF: 0.0565 AC: 14213 AN: 251454 AF XY: 0.0585

Gnomad AFR exome AF: 0.0116

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0476

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.0979

Gnomad NFE exome AF: 0.0782

Gnomad OTH exome AF: 0.0552

GnomAD4 exome AF: 0.0709 AC: 103650 AN: 1461882 Hom.: 4099 Cov.: 33 AF XY: 0.0706 AC XY: 51365 AN XY: 727238

African (AFR) AF: 0.0108 AC: 362 AN: 33480

American (AMR) AF: 0.0203 AC: 907 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 1196 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.0524 AC: 4519 AN: 86258

European-Finnish (FIN) AF: 0.0974 AC: 5204 AN: 53420

Middle Eastern (MID) AF: 0.0496 AC: 286 AN: 5768

European-Non Finnish (NFE) AF: 0.0785 AC: 87320 AN: 1112004

Other (OTH) AF: 0.0637 AC: 3847 AN: 60394

GnomAD4 genome AF: 0.0523 AC: 7945 AN: 151940 Hom.: 300 Cov.: 31 AF XY: 0.0512 AC XY: 3802 AN XY: 74258

African (AFR) AF: 0.0126 AC: 524 AN: 41444

American (AMR) AF: 0.0283 AC: 432 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0471 AC: 163 AN: 3464

East Asian (EAS) AF: 0.000970 AC: 5 AN: 5156

South Asian (SAS) AF: 0.0544 AC: 258 AN: 4746

European-Finnish (FIN) AF: 0.0898 AC: 950 AN: 10580

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0809 AC: 5498 AN: 67960

Other (OTH) AF: 0.0427 AC: 90 AN: 2110

Alfa AF: 0.0679 Hom.: 2013

Bravo AF: 0.0437

TwinsUK AF: 0.0823 AC: 305

ALSPAC AF: 0.0802 AC: 309

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.0743 AC: 639

ExAC AF: 0.0582 AC: 7061

Asia WGS AF: 0.0200 AC: 71 AN: 3478

EpiCase AF: 0.0762

EpiControl AF: 0.0742

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.94
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0047	T
MetaSVM	Uncertain	0.0020	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.96	D
Vest4		0.35
MPC		0.95
ClinPred		0.095	T
GERP RS		5.5
PromoterAI		0.034	Neutral
Varity_R		0.82
gMVP		0.86
Mutation Taster		=75/25	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11170164; hg19: chr12-52913668; COSMIC: COSV52863829; COSMIC: COSV52863829;