12-52286466-A-C

Position:

• chr12-52286466-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002281.4(KRT81):​c.1307T>G​(p.Val436Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.377

Genes affected

KRT81 (HGNC:6458): (keratin 81) The protein encoded by this gene is a member of the keratin gene family. As a type II hair keratin, it is a basic protein which heterodimerizes with type I keratins to form hair and nails. The type II hair keratins are clustered in a region of chromosome 12q13 and are grouped into two distinct subfamilies based on structure similarity. One subfamily, consisting of KRTHB1, KRTHB3, and KRTHB6, is highly related. The other less-related subfamily includes KRTHB2, KRTHB4, and KRTHB5. All hair keratins are expressed in the hair follicle; this hair keratin, as well as KRTHB3 and KRTHB6, is found primarily in the hair cortex. Mutations in this gene and KRTHB6 have been observed in patients with a rare dominant hair disease, monilethrix. Some human genome assemblies (example T2T-CHM13) have a non-coding version of the gene due to the presence of a SNP that introduces a premature stop codon after codon 281. [provided by RefSeq, Jan 2024]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.1307T>G	p.Val436Gly	missense_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10520A>C		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1	c.1307T>G	p.Val436Gly	missense_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5	c.129+10520A>C		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.1307T>G	p.Val436Gly	missense_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7	c.-5+10520A>C		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6	c.-4-15447A>C		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000654 AC: 1 AN: 153014 Hom.: 0 AF XY: 0.0000123 AC XY: 1 AN XY: 81448

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000870

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400122 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 690758

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.1307T>G (p.V436G) alteration is located in exon 9 (coding exon 9) of the KRT81 gene. This alteration results from a T to G substitution at nucleotide position 1307, causing the valine (V) at amino acid position 436 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.24	T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.51
Sift	Benign	0.077	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.31	B;.
Vest4		0.39
MutPred		0.40		Gain of catalytic residue at S431 (P = 0);Gain of catalytic residue at S431 (P = 0);
MVP		0.37
MPC		0.58
ClinPred		0.16	T
GERP RS		3.6
Varity_R		0.10
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 27

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1272049101; hg19: chr12-52680250;