12-52302256-A-G

Position:

• chr12-52302256-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5 PP3_Strong PP5

The NM_001320198.2(KRT86):​c.340A>G​(p.Asn114Asp) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N114H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 11)
• Consequence: KRT86 NM_001320198.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.08

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 12-52302256-A-G is Pathogenic according to our data. Variant chr12-52302256-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 7612.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.340A>G	p.Asn114Asp	missense_variant	3/11	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.571A>G	p.Asn191Asp	missense_variant	3/11		XP_005268923.1
KRT81	XM_047428838.1	c.-10501T>C		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.340A>G	p.Asn114Asp	missense_variant	3/11	2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000293525.5	c.340A>G	p.Asn114Asp	missense_variant	1/9	1		ENSP00000293525	P1
	ENST00000664686.1	n.252-612T>C		intron_variant, non_coding_transcript_variant
KRT86	ENST00000553310.6	c.340A>G	p.Asn114Asp	missense_variant	2/3	4		ENSP00000452237

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD4 exome Cov.: 11

GnomAD4 genome Cov.: 11

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

Aug 01, 1999

- -

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	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	.;H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	.;D;D
Vest4		1.0, 0.99
MutPred		0.83		Gain of catalytic residue at A118 (P = 0.0186);Gain of catalytic residue at A118 (P = 0.0186);Gain of catalytic residue at A118 (P = 0.0186);
MVP		0.96
MPC		2.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.58
gMVP		0.49

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: rs61091894; hg19: chr12-52696040;