chr12-52287145-C-G

Position:

• chr12-52287145-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_002281.4(KRT81):​c.1204G>C​(p.Glu402Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,613,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05

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]

KRT81 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• BS2: High AC in GnomAd4 at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT81	NM_002281.4	c.1204G>C	p.Glu402Gln	missense_variant	7/9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+11199C>G		intron_variant		ENST00000423955.7	NP_001307127.1
KRT81	XM_047428838.1	c.1204G>C	p.Glu402Gln	missense_variant	8/10
KRT86	XM_005268866.5	c.129+11199C>G		intron_variant			XP_005268923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT81	ENST00000327741.9	c.1204G>C	p.Glu402Gln	missense_variant	7/9	1	NM_002281.4	ENSP00000369349.4
KRT86	ENST00000423955.7	c.-5+11199C>G		intron_variant		2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000553310.6	c.-4-14768C>G		intron_variant		4		ENSP00000452237.3

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000486 AC: 122 AN: 251186 Hom.: 0 AF XY: 0.000479 AC XY: 65 AN XY: 135804

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000968

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00105 AC: 1534 AN: 1461166 Hom.: 1 Cov.: 32 AF XY: 0.000985 AC XY: 716 AN XY: 726880

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74484

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000646

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000981

EpiControl AF: 0.000830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.8	H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.9	D;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.96
MVP		0.96
MPC		1.2
ClinPred		0.29	T
GERP RS		5.3
Varity_R		0.85
gMVP		0.47

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: rs56821304; hg19: chr12-52680929; COSMIC: COSV99047488;