12-52286247-TG-T

Variant names:

• chr12-52286247-TG-T
• rs201146279
• NM_002281.4:c.*7delC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_002281.4(KRT81):​c.*7delC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,552,884 control chromosomes in the GnomAD database, including 19 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (15 hom.)
• Consequence: KRT81 NM_002281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.759
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 12-52286247-TG-T is Benign according to our data. Variant chr12-52286247-TG-T is described in ClinVar as Benign. ClinVar VariationId is 2643010.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 691 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.*7delC		3_prime_UTR	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10305delG		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.*7delC		3_prime_UTR	Exon 9 of 9	ENSP00000369349.4	Q14533
	KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10305delG		intron	N/A	ENSP00000444533.1	O43790
	KRT86	ENST00000958042.1		c.-5+7567delG		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 690 AN: 152144 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00456 AC: 706 AN: 154852 AF XY: 0.00501

Gnomad AFR exome AF: 0.000675

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.0138

Gnomad EAS exome AF: 0.0000838

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00534 AC: 7480 AN: 1400622 Hom.: 15 Cov.: 32 AF XY: 0.00543 AC XY: 3755 AN XY: 691168

African (AFR) AF: 0.000847 AC: 27 AN: 31894

American (AMR) AF: 0.00441 AC: 159 AN: 36086

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 405 AN: 25190

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36306

South Asian (SAS) AF: 0.00314 AC: 249 AN: 79384

European-Finnish (FIN) AF: 0.00192 AC: 94 AN: 49044

Middle Eastern (MID) AF: 0.0102 AC: 53 AN: 5186

European-Non Finnish (NFE) AF: 0.00575 AC: 6202 AN: 1079492

Other (OTH) AF: 0.00500 AC: 290 AN: 58040

GnomAD4 genome AF: 0.00454 AC: 691 AN: 152262 Hom.: 4 Cov.: 33 AF XY: 0.00485 AC XY: 361 AN XY: 74456

African (AFR) AF: 0.00115 AC: 48 AN: 41570

American (AMR) AF: 0.0105 AC: 160 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4822

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 67980

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00560 Hom.: 0

Bravo AF: 0.00482

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	KRT86-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201146279; hg19: chr12-52680031;