Variant 12-52286299-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002281.4(KRT81):c.1474T>A(p.Ser492Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,402,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Variant links:

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]

KRT81 links:

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]

KRT86 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19812506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KRT81	NM_002281.4 linkuse as main transcript	c.1474T>A	p.Ser492Thr	missense_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2 linkuse as main transcript	c.-5+10353A>T		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1 linkuse as main transcript	c.1474T>A	p.Ser492Thr	missense_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5 linkuse as main transcript	c.129+10353A>T		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
KRT81	ENST00000327741.9 linkuse as main transcript	c.1474T>A	p.Ser492Thr	missense_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7 linkuse as main transcript	c.-5+10353A>T		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6 linkuse as main transcript	c.-4-15614A>T		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1402260

Hom.:

Cov.:

AF XY:

0.00000289

AC XY:

AN XY:

691840

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.25e-7

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.1474T>A (p.S492T) alteration is located in exon 9 (coding exon 9) of the KRT81 gene. This alteration results from a T to A substitution at nucleotide position 1474, causing the serine (S) at amino acid position 492 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.026

Eigen

Benign

0.048

Eigen_PC

Benign

-0.011

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.4

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.31

REVEL

Benign

0.27

Sift

Benign

0.34

Sift4G

Benign

0.25

Polyphen

0.96

Vest4

0.21

MutPred

0.35

Gain of catalytic residue at V495 (P = 0);

MVP

0.64

MPC

0.34

ClinPred

0.28

GERP RS

4.0

Varity_R

0.038

gMVP

0.021

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over