rs121909130

Variant names:

• chr12-52306272-G-T
• rs121909130
• NM_001320198.2:c.1239G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001320198.2(KRT86):​c.1239G>T​(p.Glu413Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E413K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT86 NM_001320198.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.73
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet
• monilethrix-1

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ENSG00000287051 (HGNC:58281):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-52306270-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7609.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 12-52306272-G-T is Pathogenic according to our data. Variant chr12-52306272-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7610.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	c.1239G>T	p.Glu413Asp	missense_variant	Exon 9 of 11	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.1470G>T	p.Glu490Asp	missense_variant	Exon 9 of 11		XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT86	ENST00000423955.7	c.1239G>T	p.Glu413Asp	missense_variant	Exon 9 of 11	2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000293525.5	c.1239G>T	p.Glu413Asp	missense_variant	Exon 7 of 9	1		ENSP00000293525.5
ENSG00000287051	ENST00000664686.1	n.16C>A		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Monilethrix Pathogenic:1

Jul 01, 1998

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	0.91
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H
PhyloP100		1.7
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.77		Gain of catalytic residue at L417 (P = 0.001);Gain of catalytic residue at L417 (P = 0.001);
MVP		0.91
MPC		0.40
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.42
gMVP		0.47
Mutation Taster		=6/94	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

Other links and lift over

dbSNP: rs121909130; hg19: chr12-52700056;