Genetic Variant KRT86:p.Ala118Val (chr12-52302269-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PP3_ModerateBS1BS2

The NM_001320198.2(KRT86):c.353C>T(p.Ala118Val) variant causes a missense change involving the alteration of a conserved nucleotide. 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 0.000028 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

KRT86
NM_001320198.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.71

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 links:

ENSG00000287051 (HGNC:58281):

ENSG00000287051 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000454 (32/704316) while in subpopulation MID AF= 0.000397 (1/2516). AF 95% confidence interval is 0.0000283. There are 0 homozygotes in gnomad4_exome. There are 17 alleles in male gnomad4_exome subpopulation. Median coverage is 9. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT86	NM_001320198.2 link	c.353C>T	p.Ala118Val	missense_variant	Exon 3 of 11	ENST00000423955.7	NP_001307127.1	O43790A8K872
KRT86	XM_005268866.5 link	c.584C>T	p.Ala195Val	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>T	p.Ala118Val	missense_variant	Exon 3 of 11	2	NM_001320198.2	ENSP00000444533.1	O43790
KRT86	ENST00000293525.5 link	c.353C>T	p.Ala118Val	missense_variant	Exon 1 of 9	1		ENSP00000293525.5	O43790
KRT86	ENST00000553310.6 link	c.353C>T	p.Ala118Val	missense_variant	Exon 2 of 3	4		ENSP00000452237.3	U3KPR1
ENSG00000287051	ENST00000664686.1 link	n.252-625G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000284

AC:

AN:

70464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000610

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000540

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000640

AC:

AN:

62524

Hom.:

AF XY:

0.0000633

AC XY:

AN XY:

31606

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000762

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000284

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000434

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000454

AC:

AN:

704316

Hom.:

Cov.:

AF XY:

0.0000474

AC XY:

AN XY:

358438

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000424

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000765

Gnomad4 FIN exome

AF:

0.0000633

Gnomad4 NFE exome

AF:

0.0000425

Gnomad4 OTH exome

AF:

0.0000866

GnomAD4 genome

AF:

0.0000284

AC:

AN:

70480

Hom.:

Cov.:

AF XY:

0.0000649

AC XY:

AN XY:

30812

show subpopulations

Gnomad4 AFR

AF:

0.0000608

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000546

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

D;D;D

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

.;M;M

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.015

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.90, 0.90

MutPred

0.75

Gain of catalytic residue at I121 (P = 0.0237);Gain of catalytic residue at I121 (P = 0.0237);Gain of catalytic residue at I121 (P = 0.0237);

MVP

0.92

MPC

1.6

ClinPred

0.76

GERP RS

5.0

Varity_R

0.14

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.43

Position offset: -6

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