12-52644804-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000423.3(KRT2):c.*215C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 607,732 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.016 (70 hom.)
• Consequence: KRT2 NM_000423.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.100

Genes affected

KRT2 (HGNC:6439): (keratin 2) 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 expressed largely in the upper spinous layer of epidermal keratinocytes and mutations in this gene have been associated with bullous congenital ichthyosiform erythroderma. 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-52644804-G-A is Benign according to our data. Variant chr12-52644804-G-A is described in ClinVar as [Benign]. Clinvar id is 309592.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-52644804-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0109 (1665/152236) while in subpopulation SAS AF= 0.0206 (99/4812). AF 95% confidence interval is 0.0173. There are 22 homozygotes in gnomad4. There are 801 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1665 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT2	NM_000423.3	c.*215C>T		3_prime_UTR_variant	9/9	ENST00000309680.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT2	ENST00000309680.4	c.*215C>T		3_prime_UTR_variant	9/9	1	NM_000423.3	P1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1665 AN: 152118 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00482

Gnomad SAS AF: 0.0203

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.00959

GnomAD4 exome AF: 0.0157 AC: 7165 AN: 455496 Hom.: 70 Cov.: 5 AF XY: 0.0162 AC XY: 3913 AN XY: 241662

Gnomad4 AFR exome AF: 0.00288

Gnomad4 AMR exome AF: 0.00761

Gnomad4 ASJ exome AF: 0.00313

Gnomad4 EAS exome AF: 0.00270

Gnomad4 SAS exome AF: 0.0229

Gnomad4 FIN exome AF: 0.00657

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0109 AC: 1665 AN: 152236 Hom.: 22 Cov.: 32 AF XY: 0.0108 AC XY: 801 AN XY: 74440

Gnomad4 AFR AF: 0.00287

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00483

Gnomad4 SAS AF: 0.0206

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.00949

Alfa AF: 0.00908 Hom.: 2

Bravo AF: 0.0110

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ichthyosis bullosa of Siemens 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	3.1
Dann	Benign	0.52

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: rs117041267; hg19: chr12-53038588;