12-52286247-TG-T

Position:

• chr12-52286247-TG-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002281.4(KRT81):​c.*7del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,552,884 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (15 hom.)
• Consequence: KRT81 NM_002281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.759

Genes affected

KRT81 (HGNC:6458): (keratin 81) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin, as well as KRTHB3 and KRTHB6, is found primarily in the hair cortex. Mutations in this gene and KRTHB6 have been observed in patients with a rare dominant hair disease, monilethrix. Some human genome assemblies (example T2T-CHM13) have a non-coding version of the gene due to the presence of a SNP that introduces a premature stop codon after codon 281. [provided by RefSeq, Jan 2024]

KRT86 (HGNC:6463): (keratin 86) This gene encodes a type II keratin protein, which heterodimerizes with type I keratins to form hair and nails. This gene is present in a cluster of related genes and pseudogenes on chromosome 12. Mutations in this gene have been observed in patients with the hair disease monilethrix. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP6: Variant 12-52286247-TG-T is Benign according to our data. Variant chr12-52286247-TG-T is described in ClinVar as [Benign]. Clinvar id is 2643010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 691 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.*7del		3_prime_UTR_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10305del		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1	c.*7del		3_prime_UTR_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5	c.129+10305del		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.*7del		3_prime_UTR_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7	c.-5+10305del		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6	c.-4-15662del		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 690 AN: 152144 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00456 AC: 706 AN: 154852 Hom.: 1 AF XY: 0.00501 AC XY: 411 AN XY: 81984

Gnomad AFR exome AF: 0.000675

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.0000838

Gnomad SAS exome AF: 0.00297

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00534 AC: 7480 AN: 1400622 Hom.: 15 Cov.: 32 AF XY: 0.00543 AC XY: 3755 AN XY: 691168

Gnomad4 AFR exome AF: 0.000847

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.00314

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00575

Gnomad4 OTH exome AF: 0.00500

GnomAD4 genome AF: 0.00454 AC: 691 AN: 152262 Hom.: 4 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74456

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00560 Hom.: 0

Bravo AF: 0.00482

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

KRT86-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2022

KRT86: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201146279; hg19: chr12-52680031;