12-52287749-T-C

Variant names:

• chr12-52287749-T-C
• rs7300941
• NM_002281.4:c.901-28A>G

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.901-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 1,612,936 control chromosomes in the GnomAD database, including 211,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20103 hom., cov: 31)
  • Exomes 𝑓: 0.51 (191488 hom.)
• Consequence: KRT81 NM_002281.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-52287749-T-C is Benign according to our data. Variant chr12-52287749-T-C is described in ClinVar as [Benign]. Clinvar id is 1274144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT81	NM_002281.4	c.901-28A>G		intron_variant	Intron 5 of 8	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+11803T>C		intron_variant	Intron 2 of 10	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.129+11803T>C		intron_variant	Intron 2 of 10		XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.901-28A>G		intron_variant	Intron 5 of 8	1	NM_002281.4	ENSP00000369349.4
KRT86	ENST00000423955.7	c.-5+11803T>C		intron_variant	Intron 2 of 10	2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000553310.6	c.-4-14164T>C		intron_variant	Intron 1 of 2	4		ENSP00000452237.3

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77202 AN: 151744 Hom.: 20089 Cov.: 31

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.534

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.497

GnomAD2 exomes AF: 0.457 AC: 114592 AN: 250810 AF XY: 0.461

Gnomad AFR exome AF: 0.573

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.531

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.506 AC: 739903 AN: 1461074 Hom.: 191488 Cov.: 62 AF XY: 0.504 AC XY: 366589 AN XY: 726834

African (AFR) AF: 0.568 AC: 18994 AN: 33460

American (AMR) AF: 0.316 AC: 14105 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.460 AC: 12013 AN: 26132

East Asian (EAS) AF: 0.210 AC: 8343 AN: 39692

South Asian (SAS) AF: 0.435 AC: 37551 AN: 86234

European-Finnish (FIN) AF: 0.531 AC: 28348 AN: 53402

Middle Eastern (MID) AF: 0.425 AC: 2452 AN: 5768

European-Non Finnish (NFE) AF: 0.529 AC: 588207 AN: 1111366

Other (OTH) AF: 0.495 AC: 29890 AN: 60344

GnomAD4 genome AF: 0.509 AC: 77254 AN: 151862 Hom.: 20103 Cov.: 31 AF XY: 0.505 AC XY: 37491 AN XY: 74226

African (AFR) AF: 0.565 AC: 23383 AN: 41368

American (AMR) AF: 0.407 AC: 6222 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 1568 AN: 3468

East Asian (EAS) AF: 0.194 AC: 1000 AN: 5142

South Asian (SAS) AF: 0.429 AC: 2065 AN: 4810

European-Finnish (FIN) AF: 0.534 AC: 5627 AN: 10546

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

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

Other (OTH) AF: 0.497 AC: 1048 AN: 2110

Alfa AF: 0.507 Hom.: 3394

Bravo AF: 0.500

Asia WGS AF: 0.371 AC: 1294 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.61
PhyloP100		-1.2
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

Publications

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Other links and lift over

dbSNP: rs7300941; hg19: chr12-52681533; COSMIC: COSV59809363;