12-52306270-GAG-AAA

Variant names:

• chr12-52306270-GAG-AAA
• NM_001320198.2:c.1237_1239delGAGinsAAA
• KRT86 p.Glu413Lys

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM5 PP3

The NM_001320198.2(KRT86):​c.1237_1239delGAGinsAAA​(p.Glu413Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E413D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRT86 NM_001320198.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.63
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_001320198.2 (KRT86) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1237_1239delGAGinsAAA	p.Glu413Lys	missense	N/A	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.1237_1239delGAGinsAAA	p.Glu413Lys	missense	N/A	ENSP00000444533.1	O43790
	KRT86	ENST00000293525.5	TSL:1	c.1237_1239delGAGinsAAA	p.Glu413Lys	missense	N/A	ENSP00000293525.5	O43790
	KRT86	ENST00000958042.1		c.1237_1239delGAGinsAAA	p.Glu413Lys	missense	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

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

hg19: chr12-52700054;