rs60314569

Variant names:

• chr12-52519175-G-A
• rs60314569
• NM_000424.4:c.556-15C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-52519175-G-A
• chr12-52519175-G-T

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.556-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,613,858 control chromosomes in the GnomAD database, including 15,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2135 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13563 hom.)
• Consequence: KRT5 NM_000424.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.384
• Publications: 5 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: Orphanet, Genomics England PanelApp, Ambry Genetics
• epidermolysis bullosa simplex 2F, with mottled pigmentation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia, 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 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

ENSG00000303401 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-52519175-G-A is Benign according to our data. Variant chr12-52519175-G-A is described in ClinVar as Benign. ClinVar VariationId is 256044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 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.556-15C>T		intron	N/A	NP_000415.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT5	ENST00000252242.9	TSL:1 MANE Select	c.556-15C>T		intron	N/A	ENSP00000252242.4
	KRT5	ENST00000552629.5	TSL:1	n.654-15C>T		intron	N/A
	KRT5	ENST00000549420.1	TSL:5	c.226-15C>T		intron	N/A	ENSP00000447209.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24453 AN: 152048 Hom.: 2128 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.188

GnomAD2 exomes AF: 0.135 AC: 33891 AN: 251080 AF XY: 0.133

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0303

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.132 AC: 193020 AN: 1461692 Hom.: 13563 Cov.: 37 AF XY: 0.131 AC XY: 95309 AN XY: 727158

African (AFR) AF: 0.220 AC: 7351 AN: 33470

American (AMR) AF: 0.156 AC: 6954 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5194 AN: 26136

East Asian (EAS) AF: 0.0247 AC: 979 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8873 AN: 86254

European-Finnish (FIN) AF: 0.132 AC: 7067 AN: 53412

Middle Eastern (MID) AF: 0.191 AC: 1087 AN: 5702

European-Non Finnish (NFE) AF: 0.132 AC: 147084 AN: 1111948

Other (OTH) AF: 0.140 AC: 8431 AN: 60376

GnomAD4 genome AF: 0.161 AC: 24491 AN: 152166 Hom.: 2135 Cov.: 32 AF XY: 0.161 AC XY: 11970 AN XY: 74394

African (AFR) AF: 0.216 AC: 8978 AN: 41508

American (AMR) AF: 0.181 AC: 2767 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3470

East Asian (EAS) AF: 0.0333 AC: 172 AN: 5170

South Asian (SAS) AF: 0.103 AC: 496 AN: 4818

European-Finnish (FIN) AF: 0.126 AC: 1331 AN: 10598

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

European-Non Finnish (NFE) AF: 0.138 AC: 9362 AN: 67984

Other (OTH) AF: 0.185 AC: 391 AN: 2116

Alfa AF: 0.101 Hom.: 204

Bravo AF: 0.166

Asia WGS AF: 0.0910 AC: 318 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.4
DANN	Benign	0.69
PhyloP100		0.38
PromoterAI		-0.0010	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs60314569; hg19: chr12-52912959; COSMIC: COSV107254097; COSMIC: COSV107254097;