Genetic Variant KRT86:p.Asn114His (chr12-52302256-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM5PP3_Strong

The NM_001320198.2(KRT86):c.340A>C(p.Asn114His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N114D) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 11)

Failed GnomAD Quality Control

Consequence

KRT86
NM_001320198.2 missense

Scores

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.08

Publications

5 publications found

Variant links:

Genes affected

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 Gene-Disease associations (from GenCC):

monilethrix
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
monilethrix-1
Inheritance: AD Classification: MODERATE Submitted by: G2P

KRT86 links:

ENSG00000287051 (HGNC:58281):

ENSG00000287051 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-52302256-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 7612.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT86	NM_001320198.2 link	c.340A>C	p.Asn114His	missense_variant	Exon 3 of 11	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5 link	c.571A>C	p.Asn191His	missense_variant	Exon 3 of 11		XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
KRT86	ENST00000423955.7 link	c.340A>C	p.Asn114His	missense_variant	Exon 3 of 11	2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000293525.5 link	c.340A>C	p.Asn114His	missense_variant	Exon 1 of 9	1		ENSP00000293525.5
KRT86	ENST00000553310.6 link	c.340A>C	p.Asn114His	missense_variant	Exon 2 of 3	4		ENSP00000452237.3
ENSG00000287051	ENST00000664686.1 link	n.252-612T>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

93016

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

93016

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

42228

African (AFR)

AF:

0.00

AC:

AN:

22720

American (AMR)

AF:

0.00

AC:

AN:

8790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2588

East Asian (EAS)

AF:

0.00

AC:

AN:

3444

South Asian (SAS)

AF:

0.00

AC:

AN:

2394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

45942

Other (OTH)

AF:

0.00

AC:

AN:

1172

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

LINK: link

Submissions by phenotype

not provided

Other:1

Epithelial Biology; Institute of Medical Biology, Singapore

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

D;D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;.;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

.;H;H

PhyloP100

9.1

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.99, 0.99

MutPred

0.83

Gain of catalytic residue at A118 (P = 0.0159);Gain of catalytic residue at A118 (P = 0.0159);Gain of catalytic residue at A118 (P = 0.0159);

MVP

0.96

MPC

2.1

ClinPred

1.0

GERP RS

5.0

PromoterAI

-0.058

Neutral

(source)

Varity_R

0.59

gMVP

0.49

Mutation Taster

=2/98

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over