12-52286320-C-T

Position:

chr12-52286320-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_002281.4(KRT81):c.1453G>A(p.Val485Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,554,588 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0041 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 7 hom. )

Consequence

KRT81
NM_002281.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0250

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057397485).

BP6

Variant 12-52286320-C-T is Benign according to our data. Variant chr12-52286320-C-T is described in ClinVar as [Benign]. Clinvar id is 1701200.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000528 (741/1402230) while in subpopulation AFR AF= 0.017 (541/31840). AF 95% confidence interval is 0.0158. There are 7 homozygotes in gnomad4_exome. There are 312 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KRT81	NM_002281.4 linkuse as main transcript	c.1453G>A	p.Val485Met	missense_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2 linkuse as main transcript	c.-5+10374C>T		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1 linkuse as main transcript	c.1453G>A	p.Val485Met	missense_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5 linkuse as main transcript	c.129+10374C>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.1453G>A	p.Val485Met	missense_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7 linkuse as main transcript	c.-5+10374C>T		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6 linkuse as main transcript	c.-4-15593C>T		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes

AF:

0.00411

AC:

625

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00102

AC:

159

AN:

155904

Hom.:

AF XY:

0.000632

AC XY:

AN XY:

82264

show subpopulations

Gnomad AFR exome

AF:

0.0154

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000436

Gnomad FIN exome

AF:

0.0000643

Gnomad NFE exome

AF:

0.0000848

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000528

AC:

741

AN:

1402230

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

312

AN XY:

691884

show subpopulations

Gnomad4 AFR exome

AF:

0.0170

Gnomad4 AMR exome

AF:

0.000722

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000277

Gnomad4 SAS exome

AF:

0.0000630

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.0000824

Gnomad4 OTH exome

AF:

0.00112

GnomAD4 genome

AF:

0.00411

AC:

626

AN:

152358

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0142

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000843

Hom.:

Bravo

AF:

0.00472

ESP6500AA

AF:

0.0130

AC:

ESP6500EA

AF:

0.000236

AC:

ExAC

AF:

0.000963

AC:

107

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

KRT81: BP4, BS1, BS2; KRT86: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.024

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.39

MetaRNN

Benign

0.0057

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.080

REVEL

Benign

0.22

Sift

Benign

0.079

Sift4G

Benign

0.22

Polyphen

1.0

Vest4

0.29

MVP

0.51

MPC

0.37

ClinPred

0.030

GERP RS

3.3

Varity_R

0.027

gMVP

0.050

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over