12-52286436-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002281.4(KRT81):c.1337G>A(p.Arg446Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,552,896 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000039 (2 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05416748).
• BS2: High AC in GnomAd at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT81	NM_002281.4	c.1337G>A	p.Arg446Gln	missense_variant	9/9	ENST00000327741.9
KRT86	NM_001320198.2	c.-5+10490C>T		intron_variant		ENST00000423955.7
KRT81	XM_047428838.1	c.1337G>A	p.Arg446Gln	missense_variant	10/10
KRT86	XM_005268866.5	c.129+10490C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT81	ENST00000327741.9	c.1337G>A	p.Arg446Gln	missense_variant	9/9	1	NM_002281.4	P1
KRT86	ENST00000423955.7	c.-5+10490C>T		intron_variant		2	NM_001320198.2	P1
KRT86	ENST00000553310.6	c.-4-15477C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000104 AC: 16 AN: 154082 Hom.: 0 AF XY: 0.0000857 AC XY: 7 AN XY: 81634

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.000161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000869

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000346

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 55 AN: 1400612 Hom.: 2 Cov.: 33 AF XY: 0.0000376 AC XY: 26 AN XY: 691020

Gnomad4 AFR exome AF: 0.000915

Gnomad4 AMR exome AF: 0.000167

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000278

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.000103

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74466

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000280

ESP6500AA AF: 0.000929 AC: 4

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000547 AC: 6

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

Aug 09, 2021

The c.1337G>A (p.R446Q) alteration is located in exon 9 (coding exon 9) of the KRT81 gene. This alteration results from a G to A substitution at nucleotide position 1337, causing the arginine (R) at amino acid position 446 to be replaced by a glutamine (Q). 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	0.075
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.28	N;.
REVEL	Benign	0.26
Sift	Benign	0.33	T;.
Sift4G	Benign	0.37	T;T
Polyphen		0.065	B;.
Vest4		0.44
MVP		0.45
MPC		0.43
ClinPred		0.037	T
GERP RS		4.8
Varity_R		0.091
gMVP		0.052

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs139838048; hg19: chr12-52680220; COSMIC: COSV100576996;