NM_000424.4:c.1675C>G

Variant names:

• chr12-52515040-G-C
• rs754242209
• NM_000424.4:c.1675C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000424.4(KRT5):​c.1675C>G​(p.Arg559Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R559Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19948548).

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.1675C>G	p.Arg559Gly	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.1675C>G	p.Arg559Gly	missense	Exon 9 of 9	ENSP00000252242.4	P13647
	KRT5	ENST00000552952.1	TSL:2	n.600C>G		non_coding_transcript_exon	Exon 2 of 2
	ENSG00000303382	ENST00000794060.1		n.465-1540G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 117462 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000254 AC: 3 AN: 1182776 Hom.: 0 Cov.: 42 AF XY: 0.00000170 AC XY: 1 AN XY: 586630

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27810

American (AMR) AF: 0.00 AC: 0 AN: 38316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20164

East Asian (EAS) AF: 0.00 AC: 0 AN: 25174

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4608

European-Non Finnish (NFE) AF: 0.00000220 AC: 2 AN: 907382

Other (OTH) AF: 0.00 AC: 0 AN: 46368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 117492 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 55824

African (AFR) AF: 0.00 AC: 0 AN: 30184

American (AMR) AF: 0.00 AC: 0 AN: 10106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3030

East Asian (EAS) AF: 0.00 AC: 0 AN: 4000

South Asian (SAS) AF: 0.00 AC: 0 AN: 3380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57944

Other (OTH) AF: 0.00 AC: 0 AN: 1564

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.85
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Benign	0.26	T
Sift4G	Benign	0.63	T
Polyphen		0.20	B
Vest4		0.42
MutPred		0.30		Loss of methylation at R559 (P = 0.0087)
MVP		0.71
MPC		0.28
ClinPred		0.31	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.64
Mutation Taster		=85/15	polymorphism

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: rs754242209; hg19: chr12-52908824;