chr12-52286391-A-G

Position:

• chr12-52286391-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002281.4(KRT81):​c.1382T>C​(p.Val461Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,555,130 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16198853).
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.1382T>C	p.Val461Ala	missense_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10445A>G		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1	c.1382T>C	p.Val461Ala	missense_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5	c.129+10445A>G		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.1382T>C	p.Val461Ala	missense_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7	c.-5+10445A>G		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6	c.-4-15522A>G		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000207 AC: 29 AN: 1402952 Hom.: 0 Cov.: 33 AF XY: 0.0000217 AC XY: 15 AN XY: 692310

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: 0.0000268

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

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

Sep 20, 2023

The c.1382T>C (p.V461A) alteration is located in exon 9 (coding exon 9) of the KRT81 gene. This alteration results from a T to C substitution at nucleotide position 1382, causing the valine (V) at amino acid position 461 to be replaced by an alanine (A). 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	0.15
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.56	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.61	N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.89	N;.
REVEL	Benign	0.23
Sift	Benign	0.060	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.17	B;.
Vest4		0.14
MutPred		0.32		Gain of catalytic residue at P456 (P = 8e-04);Gain of catalytic residue at P456 (P = 8e-04);
MVP		0.53
MPC		0.45
ClinPred		0.31	T
GERP RS		4.8
Varity_R		0.087
gMVP		0.055

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: rs1336607247; hg19: chr12-52680175;