12-52286320-C-T

Variant names:

• chr12-52286320-C-T
• rs115355093
• NM_002281.4:c.1453G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_002281.4(KRT81):​c.1453G>A​(p.Val485Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000879 in 1,554,588 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (7 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0250
• Publications: 6 publications found

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]

KRT86 Gene-Disease associations (from GenCC):

• monilethrix

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet
• monilethrix-1

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057397485).
• BP6: Variant 12-52286320-C-T is Benign according to our data. Variant chr12-52286320-C-T is described in ClinVar as Benign. ClinVar VariationId is 1701200.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000528 (741/1402230) while in subpopulation AFR AF = 0.017 (541/31840). AF 95% confidence interval is 0.0158. There are 7 homozygotes in GnomAdExome4. There are 312 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 626 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT81	NM_002281.4	MANE Select	c.1453G>A	p.Val485Met	missense	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10374C>T		intron	N/A	NP_001307127.1	O43790

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT81	ENST00000327741.9	TSL:1 MANE Select	c.1453G>A	p.Val485Met	missense	Exon 9 of 9	ENSP00000369349.4	Q14533
	KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10374C>T		intron	N/A	ENSP00000444533.1	O43790
	KRT86	ENST00000958042.1		c.-5+7636C>T		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 625 AN: 152240 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00102 AC: 159 AN: 155904 AF XY: 0.000632

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000643

Gnomad NFE exome AF: 0.0000848

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000528 AC: 741 AN: 1402230 Hom.: 7 Cov.: 33 AF XY: 0.000451 AC XY: 312 AN XY: 691884

African (AFR) AF: 0.0170 AC: 541 AN: 31840

American (AMR) AF: 0.000722 AC: 26 AN: 36010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.0000277 AC: 1 AN: 36162

South Asian (SAS) AF: 0.0000630 AC: 5 AN: 79422

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49296

Middle Eastern (MID) AF: 0.00231 AC: 13 AN: 5622

European-Non Finnish (NFE) AF: 0.0000824 AC: 89 AN: 1080562

Other (OTH) AF: 0.00112 AC: 65 AN: 58122

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152358 Hom.: 3 Cov.: 33 AF XY: 0.00372 AC XY: 277 AN XY: 74512

African (AFR) AF: 0.0142 AC: 590 AN: 41582

American (AMR) AF: 0.00150 AC: 23 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00148 Hom.: 3

Bravo AF: 0.00472

ESP6500AA AF: 0.0130 AC: 56

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.000963 AC: 107

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.025
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.22
Sift	Benign	0.079	T
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.29
MVP		0.51
MPC		0.37
ClinPred		0.030	T
GERP RS		3.3
Varity_R		0.027
gMVP		0.050
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs115355093; hg19: chr12-52680104; COSMIC: COSV59809487;