chr12-52286982-G-A

Position:

• chr12-52286982-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000327741.9(KRT81):​c.1247+120C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,574,526 control chromosomes in the GnomAD database, including 2,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (877 hom., cov: 33)
  • Exomes 𝑓: 0.014 (1202 hom.)
• Consequence: KRT81 ENST00000327741.9 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.980

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-52286982-G-A is Benign according to our data. Variant chr12-52286982-G-A is described in ClinVar as [Benign]. Clinvar id is 1224979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT86	NM_001320198.2	c.-5+11036G>A		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	NM_002281.4	c.1247+120C>T		intron_variant		ENST00000327741.9	NP_002272.2
KRT86	XM_005268866.5	c.129+11036G>A		intron_variant			XP_005268923.1
KRT81	XM_047428838.1	c.1247+120C>T		intron_variant			XP_047284794.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.1247+120C>T		intron_variant		1	NM_002281.4	ENSP00000369349	P1
KRT86	ENST00000423955.7	c.-5+11036G>A		intron_variant		2	NM_001320198.2	ENSP00000444533	P1
KRT86	ENST00000553310.6	c.-4-14931G>A		intron_variant		4		ENSP00000452237

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9844 AN: 152120 Hom.: 861 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0546

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.0440

GnomAD4 exome AF: 0.0138 AC: 19595 AN: 1422288 Hom.: 1202 Cov.: 29 AF XY: 0.0144 AC XY: 10168 AN XY: 707722

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0523

Gnomad4 FIN exome AF: 0.00772

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.0247

GnomAD4 genome AF: 0.0650 AC: 9901 AN: 152238 Hom.: 877 Cov.: 33 AF XY: 0.0643 AC XY: 4785 AN XY: 74420

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.0250

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.104

Gnomad4 SAS AF: 0.0545

Gnomad4 FIN AF: 0.00989

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.00844 Hom.: 16

Bravo AF: 0.0710

Asia WGS AF: 0.0770 AC: 268 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 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.69

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: rs59448276; hg19: chr12-52680766;