12-52515010-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000424.4(KRT5):c.1705G>A(p.Gly569Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,613,172 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: KRT5 NM_000424.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009361148).
• BP6: Variant 12-52515010-C-T is Benign according to our data. Variant chr12-52515010-C-T is described in ClinVar as [Benign]. Clinvar id is 309555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00234 (356/151892) while in subpopulation AFR AF= 0.00812 (336/41402). AF 95% confidence interval is 0.0074. There are 3 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT5	NM_000424.4	c.1705G>A	p.Gly569Arg	missense_variant	9/9	ENST00000252242.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT5	ENST00000252242.9	c.1705G>A	p.Gly569Arg	missense_variant	9/9	1	NM_000424.4	P1
KRT5	ENST00000552952.1	n.630G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 356 AN: 151774 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00814

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000658 AC: 164 AN: 249404 Hom.: 0 AF XY: 0.000422 AC XY: 57 AN XY: 134994

Gnomad AFR exome AF: 0.00833

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000227 AC: 332 AN: 1461280 Hom.: 2 Cov.: 31 AF XY: 0.000180 AC XY: 131 AN XY: 726890

Gnomad4 AFR exome AF: 0.00687

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.00234 AC: 356 AN: 151892 Hom.: 3 Cov.: 31 AF XY: 0.00218 AC XY: 162 AN XY: 74264

Gnomad4 AFR AF: 0.00812

Gnomad4 AMR AF: 0.000721

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000536 Hom.: 1

Bravo AF: 0.00271

ESP6500AA AF: 0.00749 AC: 33

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000791 AC: 96

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epidermolysis bullosa simplex Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.073
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0094	T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.39
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		0.038	T
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;