rs121912474

Positions:

• chr12-52520277-A-G
• chr12-52520277-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The ENST00000252242.9(KRT5):​c.20T>C​(p.Val7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT5 ENST00000252242.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.34

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-52520277-A-G is Pathogenic according to our data. Variant chr12-52520277-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14646.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22348458). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT5	NM_000424.4	c.20T>C	p.Val7Ala	missense_variant	1/9	ENST00000252242.9	NP_000415.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT5	ENST00000252242.9	c.20T>C	p.Val7Ala	missense_variant	1/9	1	NM_000424.4	ENSP00000252242	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epidermolysis bullosa simplex 2B, generalized intermediate Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;.;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.27	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L;.;.;.
MutationTaster	Benign	2.6e-9	A
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.13	T;T;D;D
Sift4G	Benign	0.50	T;.;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.20
MutPred		0.28		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.54
MPC		0.26
ClinPred		0.17	T
GERP RS		3.6
Varity_R		0.064
gMVP		0.44

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: rs121912474; hg19: chr12-52914061;