12-52302269-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_001320198.2(KRT86):c.353C>A(p.Ala118Glu) 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 Pathogenic (no stars).

Frequency

Genomes: not found (cov: 9)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRT86
NM_001320198.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 7.71

Publications

2 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: Uncertain_significance. The variant received 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 12-52302269-C-A is Pathogenic according to our data. Variant chr12-52302269-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7614.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT86	NM_001320198.2 link	c.353C>A	p.Ala118Glu	missense_variant	Exon 3 of 11	ENST00000423955.7	NP_001307127.1	O43790A8K872
KRT86	XM_005268866.5 link	c.584C>A	p.Ala195Glu	missense_variant	Exon 3 of 11		XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT86	ENST00000423955.7 link	c.353C>A	p.Ala118Glu	missense_variant	Exon 3 of 11	2	NM_001320198.2	ENSP00000444533.1	O43790
KRT86	ENST00000293525.5 link	c.353C>A	p.Ala118Glu	missense_variant	Exon 1 of 9	1		ENSP00000293525.5	O43790
KRT86	ENST00000553310.6 link	c.353C>A	p.Ala118Glu	missense_variant	Exon 2 of 3	4		ENSP00000452237.3	U3KPR1
ENSG00000287051	ENST00000664686.1 link	n.252-625G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000142

AC:

AN:

704322

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358444

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

17878

American (AMR)

AF:

0.00

AC:

AN:

23608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16056

East Asian (EAS)

AF:

0.00

AC:

AN:

32130

South Asian (SAS)

AF:

0.00

AC:

AN:

52276

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2516

European-Non Finnish (NFE)

AF:

0.00000203

AC:

AN:

493644

Other (OTH)

AF:

0.00

AC:

AN:

34628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Monilethrix

Pathogenic:1

Sep 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

0.97

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

D;D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

.;H;H

PhyloP100

7.7

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.97

MutPred

0.79

Gain of catalytic residue at I121 (P = 0.0177);Gain of catalytic residue at I121 (P = 0.0177);Gain of catalytic residue at I121 (P = 0.0177);

MVP

0.93

MPC

2.1

ClinPred

1.0

GERP RS

5.0

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.65

gMVP

0.32

Mutation Taster

=11/89

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over