12-52306237-G-C

Variant names:

• chr12-52306237-G-C
• rs60687604
• NM_001320198.2:c.1204G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001320198.2(KRT86):​c.1204G>C​(p.Glu402Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,362 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT86 NM_001320198.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.88

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]

ENSG00000287051 (HGNC:58281):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955
• PP5: Variant 12-52306237-G-C is Pathogenic according to our data. Variant chr12-52306237-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7613.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.1204G>C	p.Glu402Gln	missense_variant	Exon 9 of 11	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.1435G>C	p.Glu479Gln	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.1204G>C	p.Glu402Gln	missense_variant	Exon 9 of 11	2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000293525.5	c.1204G>C	p.Glu402Gln	missense_variant	Exon 7 of 9	1		ENSP00000293525.5
ENSG00000287051	ENST00000664686.1	n.51C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461362 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726980

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Beaded hair Pathogenic:1

Dec 01, 1999

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	0.88
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.98
MutPred		0.79		Gain of catalytic residue at L397 (P = 0.0021);Gain of catalytic residue at L397 (P = 0.0021);
MVP		0.99
MPC		0.71
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.58
gMVP		0.61

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: rs60687604; hg19: chr12-52700021;