12-52519122-G-T

Variant names:

• chr12-52519122-G-T
• rs641621
• NM_000424.4:c.594C>A

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.594C>A​(p.Thr198Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.261 in 1,610,090 control chromosomes in the GnomAD database, including 55,896 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T198T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.23 (4483 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51413 hom.)
• Consequence: KRT5 NM_000424.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 4.53
• Publications: 12 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

ENSG00000303401 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-52519122-G-T is Benign according to our data. Variant chr12-52519122-G-T is described in ClinVar as Benign. ClinVar VariationId is 66277.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 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.594C>A	p.Thr198Thr	synonymous	Exon 2 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.594C>A	p.Thr198Thr	synonymous	Exon 2 of 9	ENSP00000252242.4	P13647
	KRT5	ENST00000552629.5	TSL:1	n.692C>A		non_coding_transcript_exon	Exon 2 of 7
	KRT5	ENST00000549420.1	TSL:5	c.264C>A	p.Thr88Thr	synonymous	Exon 3 of 5	ENSP00000447209.1	F8W0C6

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34896 AN: 151900 Hom.: 4483 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.237

GnomAD2 exomes AF: 0.247 AC: 60894 AN: 246716 AF XY: 0.246

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.329

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.265 AC: 386031 AN: 1458072 Hom.: 51413 Cov.: 83 AF XY: 0.263 AC XY: 190846 AN XY: 725528

African (AFR) AF: 0.126 AC: 4222 AN: 33466

American (AMR) AF: 0.271 AC: 12104 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 7061 AN: 26106

East Asian (EAS) AF: 0.388 AC: 15371 AN: 39616

South Asian (SAS) AF: 0.180 AC: 15495 AN: 86206

European-Finnish (FIN) AF: 0.237 AC: 12656 AN: 53364

Middle Eastern (MID) AF: 0.307 AC: 1766 AN: 5750

European-Non Finnish (NFE) AF: 0.273 AC: 302214 AN: 1108638

Other (OTH) AF: 0.251 AC: 15142 AN: 60280

GnomAD4 genome AF: 0.230 AC: 34894 AN: 152018 Hom.: 4483 Cov.: 32 AF XY: 0.226 AC XY: 16809 AN XY: 74286

African (AFR) AF: 0.133 AC: 5509 AN: 41518

American (AMR) AF: 0.257 AC: 3926 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 925 AN: 3468

East Asian (EAS) AF: 0.357 AC: 1843 AN: 5168

South Asian (SAS) AF: 0.180 AC: 865 AN: 4814

European-Finnish (FIN) AF: 0.236 AC: 2493 AN: 10564

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18530 AN: 67900

Other (OTH) AF: 0.236 AC: 498 AN: 2112

Alfa AF: 0.248 Hom.: 2119

Bravo AF: 0.231

Asia WGS AF: 0.234 AC: 814 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	Epidermolysis bullosa simplex 1A, generalized severe;C0432316:Epidermolysis bullosa simplex with mottled pigmentation;C1836284:Epidermolysis bullosa simplex with migratory circinate erythema;C4552092:Dowling-Degos disease 1;C5562009:Epidermolysis bullosa simplex 2B, generalized intermediate;C5562011:Epidermolysis bullosa simplex 2C, localized;C5562014:Epidermolysis bullosa simplex 2d, generalized, intermediate or severe, autosomal recessive;CN301077:Epidermolysis bullosa simplex 2A, generalized severe (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		4.5
PromoterAI		-0.0080	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: rs641621; hg19: chr12-52912906; COSMIC: COSV52858836; COSMIC: COSV52858836;