rs60612575

Variant names:

• chr12-52302269-C-A
• rs60612575
• NM_001320198.2:c.353C>A
• KRT86 p.Ala118Glu

Your query was ambiguous. Multiple possible variants found:

• chr12-52302269-C-A
• chr12-52302269-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_Strong PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.71
• Publications: 2 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• monilethrix-1

  Inheritance: AD Classification: MODERATE Submitted by: G2P

KRT86-AS1 (HGNC:58281):

ACMG classification

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

Sel.	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.: 9

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000142 AC: 1 AN: 704322 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 358444

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

African (AFR) AF: 0.00 AC: 0 AN: 17878

American (AMR) AF: 0.00 AC: 0 AN: 23608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16056

East Asian (EAS) AF: 0.00 AC: 0 AN: 32130

South Asian (SAS) AF: 0.00 AC: 0 AN: 52276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2516

European-Non Finnish (NFE) AF: 0.00000203 AC: 1 AN: 493644

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 9

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	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	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		7.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.018	Neutral
Varity_R		0.65
gMVP		0.32
Mutation Taster		=11/89	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs60612575;

hg19: chr12-52696053;