chr12-52286153-C-G

Position:

• chr12-52286153-C-G

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.*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

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 (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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.*102G>C		3_prime_UTR_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10207C>G		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1	c.*102G>C		3_prime_UTR_variant	10/10		XP_047284794.1
KRT86	XM_005268866.5	c.129+10207C>G		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.*102G>C		3_prime_UTR_variant	9/9	1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7	c.-5+10207C>G		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6	c.-4-15760C>G		intron_variant		4		ENSP00000452237

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

Gnomad4 AFR exome AF: 0.543

Gnomad4 AMR exome AF: 0.323

Gnomad4 ASJ exome AF: 0.461

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.531

Gnomad4 NFE exome AF: 0.522

Gnomad4 OTH exome AF: 0.489

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

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.483

Alfa AF: 0.512 Hom.: 2240

Bravo AF: 0.494

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	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 32678982, 25716425, 22539802, 23613771, 24530479) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.8
DANN	Benign	0.65

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: rs3660; hg19: chr12-52679937;