12-52360984-G-A

Position:

• chr12-52360984-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002283.4(KRT85):​c.1393C>T​(p.Arg465Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,613,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: KRT85 NM_002283.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

Genes affected

KRT85 (HGNC:6462): (keratin 85) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09670749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT85	NM_002283.4	c.1393C>T	p.Arg465Cys	missense_variant	9/9	ENST00000257901.7	NP_002274.1
KRT85	NM_001300810.1	c.757C>T	p.Arg253Cys	missense_variant	7/7		NP_001287739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT85	ENST00000257901.7	c.1393C>T	p.Arg465Cys	missense_variant	9/9	1	NM_002283.4	ENSP00000257901.3
KRT85	ENST00000544265.1	c.757C>T	p.Arg253Cys	missense_variant	7/7	2		ENSP00000440240.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000165 AC: 41 AN: 248196 Hom.: 0 AF XY: 0.000156 AC XY: 21 AN XY: 134568

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461302 Hom.: 0 Cov.: 32 AF XY: 0.000171 AC XY: 124 AN XY: 726932

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152284 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74456

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 465 of the KRT85 protein (p.Arg465Cys). This variant is present in population databases (rs201777129, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with KRT85-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KRT85 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-0.28	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.25
Sift	Benign	0.077	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.97	D;.
Vest4		0.21
MVP		0.92
MPC		0.45
ClinPred		0.030	T
GERP RS		3.2
Varity_R		0.065
gMVP		0.52

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: rs201777129; hg19: chr12-52754768;