12-52302269-C-A

Position:

• chr12-52302269-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 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 id is 7614.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT86	NM_001320198.2	c.353C>A	p.Ala118Glu	missense_variant	3/11	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.584C>A	p.Ala195Glu	missense_variant	3/11		XP_005268923.1
KRT81	XM_047428838.1	c.-10514G>T		5_prime_UTR_variant	1/10		XP_047284794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT86	ENST00000423955.7	c.353C>A	p.Ala118Glu	missense_variant	3/11	2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000293525.5	c.353C>A	p.Ala118Glu	missense_variant	1/9	1		ENSP00000293525	P1
	ENST00000664686.1	n.252-625G>T		intron_variant, non_coding_transcript_variant
KRT86	ENST00000553310.6	c.353C>A	p.Ala118Glu	missense_variant	2/3	4		ENSP00000452237

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000203

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 9

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Beaded hair Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;H;H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.97
MutPred		0.79		Gain of catalytic residue at I121 (P = 0.0177);Gain of catalytic residue at I121 (P = 0.0177);Gain of catalytic residue at I121 (P = 0.0177);
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.65
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs60612575; hg19: chr12-52696053;