chr12-52286224-T-C

Position:

• chr12-52286224-T-C

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.*31A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,534,656 control chromosomes in the GnomAD database, including 198,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18135 hom., cov: 33)
  • Exomes 𝑓: 0.51 (180593 hom.)
• Consequence: KRT81 NM_002281.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.71

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=-0.87).
• BP6: Variant 12-52286224-T-C is Benign according to our data. Variant chr12-52286224-T-C is described in ClinVar as [Benign]. Clinvar id is 1273289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.*31A>G		3_prime_UTR_variant	9/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10278T>C		intron_variant		ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.129+10278T>C		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741	c.*31A>G		3_prime_UTR_variant	9/9	1	NM_002281.4	ENSP00000369349.4
KRT86	ENST00000423955.7	c.-5+10278T>C		intron_variant		2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000553310.6	c.-4-15689T>C		intron_variant		4		ENSP00000452237.3

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73473 AN: 151894 Hom.: 18127 Cov.: 33

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.453

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.474

GnomAD3 exomes AF: 0.442 AC: 67696 AN: 153324 Hom.: 16082 AF XY: 0.445 AC XY: 36099 AN XY: 81130

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.431

Gnomad FIN exome AF: 0.530

Gnomad NFE exome AF: 0.523

Gnomad OTH exome AF: 0.459

GnomAD4 exome AF: 0.506 AC: 699278 AN: 1382644 Hom.: 180593 Cov.: 26 AF XY: 0.503 AC XY: 343819 AN XY: 683094

Gnomad4 AFR exome AF: 0.476

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.460

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.433

Gnomad4 FIN exome AF: 0.531

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.484 AC: 73505 AN: 152012 Hom.: 18135 Cov.: 33 AF XY: 0.481 AC XY: 35712 AN XY: 74282

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.398

Gnomad4 ASJ AF: 0.453

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.427

Gnomad4 FIN AF: 0.532

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.474

Alfa AF: 0.490 Hom.: 6922

Bravo AF: 0.472

Asia WGS AF: 0.366 AC: 1276 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
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.26
DANN	Benign	0.50

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: rs3657; hg19: chr12-52680008; COSMIC: COSV59810361; COSMIC: COSV59810361;