12-52515039-C-G

Variant names:

• chr12-52515039-C-G
• rs182482982
• NM_000424.4:c.1676G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000424.4(KRT5):​c.1676G>C​(p.Arg559Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 150,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.492

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29212624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4	c.1676G>C	p.Arg559Pro	missense_variant	Exon 9 of 9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.1676G>C	p.Arg559Pro	missense_variant	Exon 9 of 9	1	NM_000424.4	ENSP00000252242.4
KRT5	ENST00000552952.1	n.601G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
KRT5	ENST00000549511.5	n.*74G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 150980 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000244

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 Cov.: 46

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 150980 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 73700

Gnomad4 AFR AF: 0.0000244

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.43
Sift	Benign	0.18	T
Sift4G	Benign	0.31	T
Polyphen		0.64	P
Vest4		0.41
MutPred		0.32		Loss of methylation at R559 (P = 0.0087);
MVP		0.76
MPC		0.31
ClinPred		0.39	T
GERP RS		3.6
Varity_R		0.35
gMVP		0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs182482982; hg19: chr12-52908823;