NM_001320198.2:c.353C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PM5PP3_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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A118E) has been classified as Pathogenic.

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

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: Likely_benign. The variant received -4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 17 alleles in the male GnomAdExome4 subpopulation. Median coverage is 9. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 32 AD gene.

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>T	p.Ala118Val	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>T	p.Ala118Val	missense	Exon 3 of 11	ENSP00000444533.1	O43790
KRT86	ENST00000293525.5	TSL:1	c.353C>T	p.Ala118Val	missense	Exon 1 of 9	ENSP00000293525.5	O43790
KRT86	ENST00000958042.1		c.353C>T	p.Ala118Val	missense	Exon 2 of 10	ENSP00000628101.1

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

GnomAD2 exomes

AF:

0.0000640

AC:

AN:

62524

AF XY:

0.0000633

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 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

African (AFR)

AF:

0.00

AC:

AN:

17878

American (AMR)

AF:

0.0000424

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:

0.0000765

AC:

AN:

52276

European-Finnish (FIN)

AF:

0.0000633

AC:

AN:

31586

Middle Eastern (MID)

AF:

0.000397

AC:

AN:

2516

European-Non Finnish (NFE)

AF:

0.0000425

AC:

AN:

493638

Other (OTH)

AF:

0.0000866

AC:

AN:

34628

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

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

AF:

0.0000284

AC:

AN:

70480

Hom.:

Cov.:

AF XY:

0.0000649

AC XY:

AN XY:

30812

show subpopulations

African (AFR)

AF:

0.0000608

AC:

AN:

16456

American (AMR)

AF:

0.00

AC:

AN:

6520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2168

East Asian (EAS)

AF:

0.00

AC:

AN:

2872

South Asian (SAS)

AF:

0.000546

AC:

AN:

1832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

226

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

35506

Other (OTH)

AF:

0.00

AC:

AN:

894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000843

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

PhyloP100

7.7

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.015

Polyphen

1.0

Vest4

0.90

MutPred

0.75

Gain of catalytic residue at I121 (P = 0.0237)

MVP

0.92

MPC

1.6

ClinPred

0.76

GERP RS

5.0

PromoterAI

-0.0046

Neutral

(source)

Varity_R

0.14

gMVP

0.12

Mutation Taster

=40/60

disease causing

(source)

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

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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