Variant 12-52286475-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002281.4(KRT81):c.1298G>A(p.Gly433Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000258 in 1,552,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.744

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT81	NM_002281.4 link	c.1298G>A	p.Gly433Asp	missense_variant	Exon 9 of 9	ENST00000327741.9	NP_002272.2	Q14533
KRT86	NM_001320198.2 link	c.-5+10529C>T		intron_variant	Intron 2 of 10	ENST00000423955.7	NP_001307127.1	O43790A8K872
KRT86	XM_005268866.5 link	c.129+10529C>T		intron_variant	Intron 2 of 10		XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT81	ENST00000327741.9 link	c.1298G>A	p.Gly433Asp	missense_variant	Exon 9 of 9	1	NM_002281.4	ENSP00000369349.4	Q14533
KRT86	ENST00000423955.7 link	c.-5+10529C>T		intron_variant	Intron 2 of 10	2	NM_001320198.2	ENSP00000444533.1	O43790
KRT86	ENST00000553310.6 link	c.-4-15438C>T		intron_variant	Intron 1 of 2	4		ENSP00000452237.3	U3KPR1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000653

AC:

AN:

153028

Hom.:

AF XY:

0.00

AC XY:

AN XY:

81514

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1400132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

690758

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:

0.00000278

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.45

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.74

D;D

MetaSVM

Uncertain

0.42

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.0

D;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

D;.

Vest4

0.60

MutPred

0.45

Gain of catalytic residue at S431 (P = 0);Gain of catalytic residue at S431 (P = 0);

MVP

0.70

MPC

1.2

ClinPred

0.97

GERP RS

4.8

Varity_R

0.70

gMVP

0.19

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over