12-52286153-C-G

Variant names:

• chr12-52286153-C-G
• rs3660
• NM_002281.4:c.*102G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002281.4(KRT81):​c.*102G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 925,972 control chromosomes in the GnomAD database, including 115,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19625 hom., cov: 32)
  • Exomes 𝑓: 0.49 (96127 hom.)
• Consequence: KRT81 NM_002281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.116
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-52286153-C-G is Benign according to our data. Variant chr12-52286153-C-G is described in ClinVar as Benign. ClinVar VariationId is 1253561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 is higher than 0.05.

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.*102G>C		3_prime_UTR	Exon 9 of 9	NP_002272.2	Q14533
	KRT86	NM_001320198.2	MANE Select	c.-5+10207C>G		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.*102G>C		3_prime_UTR	Exon 9 of 9	ENSP00000369349.4	Q14533
	KRT86	ENST00000423955.7	TSL:2 MANE Select	c.-5+10207C>G		intron	N/A	ENSP00000444533.1	O43790
	KRT86	ENST00000958042.1		c.-5+7469C>G		intron	N/A	ENSP00000628101.1

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76468 AN: 151914 Hom.: 19613 Cov.: 32

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.426

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.483

GnomAD4 exome AF: 0.490 AC: 379302 AN: 773940 Hom.: 96127 Cov.: 10 AF XY: 0.488 AC XY: 196015 AN XY: 402030

African (AFR) AF: 0.543 AC: 10513 AN: 19364

American (AMR) AF: 0.323 AC: 11089 AN: 34280

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 9625 AN: 20898

East Asian (EAS) AF: 0.213 AC: 6988 AN: 32824

South Asian (SAS) AF: 0.433 AC: 28445 AN: 65754

European-Finnish (FIN) AF: 0.531 AC: 25390 AN: 47806

Middle Eastern (MID) AF: 0.437 AC: 1258 AN: 2876

European-Non Finnish (NFE) AF: 0.522 AC: 267853 AN: 513006

Other (OTH) AF: 0.489 AC: 18141 AN: 37132

GnomAD4 genome AF: 0.503 AC: 76504 AN: 152032 Hom.: 19625 Cov.: 32 AF XY: 0.499 AC XY: 37102 AN XY: 74312

African (AFR) AF: 0.545 AC: 22596 AN: 41446

American (AMR) AF: 0.405 AC: 6199 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.453 AC: 1571 AN: 3470

East Asian (EAS) AF: 0.202 AC: 1039 AN: 5154

South Asian (SAS) AF: 0.427 AC: 2062 AN: 4832

European-Finnish (FIN) AF: 0.533 AC: 5644 AN: 10582

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35563 AN: 67940

Other (OTH) AF: 0.483 AC: 1020 AN: 2112

Alfa AF: 0.512 Hom.: 2240

Bravo AF: 0.494

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.8
DANN	Benign	0.65
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3660; hg19: chr12-52679937;