Genetic Variant KRT86:p.Ala118Glu (chr12-52302269-C-A) – ACMG Classification: Uncertain_significance (5 pts)

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

KRT86 links:

KRT86-AS1 (HGNC:58281):

KRT86-AS1 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320198.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT86	NM_001320198.2	MANE Select	c.353C>A	p.Ala118Glu	missense	Exon 3 of 11	NP_001307127.1	O43790

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRT86	ENST00000423955.7	TSL:2 MANE Select	c.353C>A	p.Ala118Glu	missense	Exon 3 of 11	ENSP00000444533.1	O43790
KRT86	ENST00000293525.5	TSL:1	c.353C>A	p.Ala118Glu	missense	Exon 1 of 9	ENSP00000293525.5	O43790
KRT86	ENST00000958042.1		c.353C>A	p.Ala118Glu	missense	Exon 2 of 10	ENSP00000628101.1

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

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Monilethrix (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.4

PhyloP100

7.7

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.79

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over