12-52515010-C-G

Variant names:

• chr12-52515010-C-G
• rs148276250
• NM_000424.4:c.1705G>C

Variant summary

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

The NM_000424.4(KRT5):​c.1705G>C​(p.Gly569Arg) 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 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80

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=0.368699).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT5	NM_000424.4	c.1705G>C	p.Gly569Arg	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.1705G>C	p.Gly569Arg	missense_variant	Exon 9 of 9	1	NM_000424.4	ENSP00000252242.4
KRT5	ENST00000552952.1	n.630G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2
KRT5	ENST00000549511.5	n.*103G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134994

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461280 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726890

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	0.0053	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.082
Eigen_PC	Benign	-0.029
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.40
Sift	Benign	0.32	T
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.34		Gain of MoRF binding (P = 0.0035);
MVP		0.85
MPC		0.26
ClinPred		0.73	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.54

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: rs148276250; hg19: chr12-52908794;