rs1012819149

Variant names:

• chr12-52286349-T-C
• rs1012819149
• NM_002281.4:c.1424A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-52286349-T-C
• chr12-52286349-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002281.4(KRT81):​c.1424A>G​(p.Asn475Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KRT81 NM_002281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.426

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035222024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT81	NM_002281.4	c.1424A>G	p.Asn475Ser	missense_variant	Exon 9 of 9	ENST00000327741.9	NP_002272.2
KRT86	NM_001320198.2	c.-5+10403T>C		intron_variant	Intron 2 of 10	ENST00000423955.7	NP_001307127.1
KRT86	XM_005268866.5	c.129+10403T>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.1424A>G	p.Asn475Ser	missense_variant	Exon 9 of 9	1	NM_002281.4	ENSP00000369349.4
KRT86	ENST00000423955.7	c.-5+10403T>C		intron_variant	Intron 2 of 10	2	NM_001320198.2	ENSP00000444533.1
KRT86	ENST00000553310.6	c.-4-15564T>C		intron_variant	Intron 1 of 2	4		ENSP00000452237.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1402790 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 692252

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.010
DANN	Benign	0.40
DEOGEN2	Benign	0.017	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.20	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.071
Sift	Benign	0.64	T
Sift4G	Benign	0.70	T
Polyphen		0.0010	B
Vest4		0.059
MVP		0.085
MPC		0.30
ClinPred		0.041	T
GERP RS		-4.7
Varity_R		0.019
gMVP		0.027

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: rs1012819149; hg19: chr12-52680133;