chr12-52806800-T-C

Position:

• chr12-52806800-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002272.4(KRT4):​c.*269A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.84 in 538,328 control chromosomes in the GnomAD database, including 190,335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52500 hom., cov: 31)
  • Exomes 𝑓: 0.84 (137835 hom.)
• Consequence: KRT4 NM_002272.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.771

Genes affected

KRT4 (HGNC:6441): (keratin 4) 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 differentiated layers of the mucosal and esophageal epithelia with family member KRT13. Mutations in these genes have been associated with White Sponge Nevus, characterized by oral, esophageal, and anal leukoplakia. 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 (BayesDel_noAF=-0.65).
• BP6: Variant 12-52806800-T-C is Benign according to our data. Variant chr12-52806800-T-C is described in ClinVar as [Benign]. Clinvar id is 66516.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.894 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT4	NM_002272.4	c.*269A>G		3_prime_UTR_variant	9/9	ENST00000551956.2	NP_002263.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT4	ENST00000551956	c.*269A>G		3_prime_UTR_variant	9/9	1	NM_002272.4	ENSP00000448220.1
KRT4	ENST00000548097.5	n.*1344A>G		non_coding_transcript_exon_variant	9/9	1		ENSP00000449755.1
KRT4	ENST00000548097.5	n.*1344A>G		3_prime_UTR_variant	9/9	1		ENSP00000449755.1

Frequencies

GnomAD3 genomes AF: 0.830 AC: 126184 AN: 152016 Hom.: 52454 Cov.: 31

Gnomad AFR AF: 0.784

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.796

Gnomad ASJ AF: 0.883

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.880

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.847

Gnomad OTH AF: 0.813

GnomAD4 exome AF: 0.844 AC: 325885 AN: 386194 Hom.: 137835 Cov.: 3 AF XY: 0.843 AC XY: 172447 AN XY: 204610

Gnomad4 AFR exome AF: 0.786

Gnomad4 AMR exome AF: 0.775

Gnomad4 ASJ exome AF: 0.877

Gnomad4 EAS exome AF: 0.885

Gnomad4 SAS exome AF: 0.824

Gnomad4 FIN exome AF: 0.882

Gnomad4 NFE exome AF: 0.847

Gnomad4 OTH exome AF: 0.842

GnomAD4 genome AF: 0.830 AC: 126287 AN: 152134 Hom.: 52500 Cov.: 31 AF XY: 0.828 AC XY: 61597 AN XY: 74356

Gnomad4 AFR AF: 0.784

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.883

Gnomad4 EAS AF: 0.916

Gnomad4 SAS AF: 0.851

Gnomad4 FIN AF: 0.880

Gnomad4 NFE AF: 0.847

Gnomad4 OTH AF: 0.814

Alfa AF: 0.838 Hom.: 70803

Bravo AF: 0.823

Asia WGS AF: 0.875 AC: 3042 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

White sponge nevus 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.65
CADD	Benign	7.7
DANN	Benign	0.80

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: rs2035879; hg19: chr12-53200584;