chr12-52520223-G-A

Variant names:

• chr12-52520223-G-A
• rs57499817
• NM_000424.4:c.74C>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_000424.4(KRT5):​c.74C>T​(p.Pro25Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001813265: Published functional studies demonstrate that although P25L does not interfere with alignment and assembly of keratin intermediate filaments, it affects the length and uniformity of the resulting filaments, thus explaining the milder blistering phenotype of EBS-MP (Uttam et al., 1996);".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:2
• Conservation: PhyloP100: 3.08
• Publications: 32 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001813265: Published functional studies demonstrate that although P25L does not interfere with alignment and assembly of keratin intermediate filaments, it affects the length and uniformity of the resulting filaments, thus explaining the milder blistering phenotype of EBS-MP (Uttam et al., 1996)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 12-52520223-G-A is Pathogenic according to our data. Variant chr12-52520223-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 14648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.74C>T	p.Pro25Leu	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.74C>T	p.Pro25Leu	missense	Exon 1 of 9	ENSP00000252242.4	P13647
	KRT5	ENST00000552629.5	TSL:1	n.172C>T		non_coding_transcript_exon	Exon 1 of 7
	KRT5	ENST00000551275.1	TSL:4	c.74C>T	p.Pro25Leu	missense	Exon 1 of 2	ENSP00000448041.1	F8VU69

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461762 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Epidermolysis bullosa simplex with mottled pigmentation (3)
2	-	-	not provided (3)
1	-	-	Epidermolysis bullosa simplex (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	KRT5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0090
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.41
Sift	Benign	0.086	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.71
MutPred		0.76		Gain of sheet (P = 0.0028)
MVP		0.69
MPC		0.63
ClinPred		0.99	D
GERP RS		5.1
PromoterAI		0.010	Neutral
Varity_R		0.17
gMVP		0.54
Mutation Taster		=33/67	disease causing (ClinVar)

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: rs57499817; hg19: chr12-52914007;