12-52286388-G-A

Position:

• chr12-52286388-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002281.4(KRT81):​c.1385C>T​(p.Ala462Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,555,306 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (102 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.415

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017445982).
• BP6: Variant 12-52286388-G-A is Benign according to our data. Variant chr12-52286388-G-A is described in ClinVar as [Benign]. Clinvar id is 1264106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.1385C>T	p.Ala462Val	missense_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10442G>A		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1	c.1385C>T	p.Ala462Val	missense_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5	c.129+10442G>A		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.1385C>T	p.Ala462Val	missense_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7	c.-5+10442G>A		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6	c.-4-15525G>A		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3298 AN: 152176 Hom.: 118 Cov.: 33

Gnomad AFR AF: 0.0745

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.00521 AC: 824 AN: 158094 Hom.: 25 AF XY: 0.00369 AC XY: 309 AN XY: 83656

Gnomad AFR exome AF: 0.0751

Gnomad AMR exome AF: 0.00358

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000914

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000429

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00229 AC: 3212 AN: 1403012 Hom.: 102 Cov.: 33 AF XY: 0.00197 AC XY: 1361 AN XY: 692386

Gnomad4 AFR exome AF: 0.0767

Gnomad4 AMR exome AF: 0.00478

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.000957

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.0217 AC: 3310 AN: 152294 Hom.: 120 Cov.: 33 AF XY: 0.0210 AC XY: 1567 AN XY: 74476

Gnomad4 AFR AF: 0.0746

Gnomad4 AMR AF: 0.00922

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.00126 Hom.: 6

Bravo AF: 0.0243

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00466 AC: 521

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.030	N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.45	N;.
REVEL	Benign	0.20
Sift	Benign	0.60	T;.
Sift4G	Benign	0.68	T;T
Polyphen		0.0040	B;.
Vest4		0.13
MVP		0.31
MPC		0.37
ClinPred		0.0027	T
GERP RS		2.3
Varity_R		0.026
gMVP		0.056

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: rs74095618; hg19: chr12-52680172;