chr12-52314636-G-A

Position:

• chr12-52314636-G-A

Variant summary

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

The NM_002282.3(KRT83):​c.1477C>T​(p.His493Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 1,562,540 control chromosomes in the GnomAD database, including 357,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (41368 hom., cov: 33)
  • Exomes 𝑓: 0.67 (315683 hom.)
• Consequence: KRT83 NM_002282.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.940

Genes affected

KRT83 (HGNC:6460): (keratin 83) 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 KRTHB1 and KRTHB6, is found primarily in the hair cortex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.666862E-7).
• BP6: Variant 12-52314636-G-A is Benign according to our data. Variant chr12-52314636-G-A is described in ClinVar as [Benign]. Clinvar id is 309494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-52314636-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT83	NM_002282.3	c.1477C>T	p.His493Tyr	missense_variant	9/9	ENST00000293670.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT83	ENST00000293670.3	c.1477C>T	p.His493Tyr	missense_variant	9/9	1	NM_002282.3	P1

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110441 AN: 151978 Hom.: 41308 Cov.: 33

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.629

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.682

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.655

Gnomad OTH AF: 0.695

GnomAD3 exomes AF: 0.653 AC: 114152 AN: 174816 Hom.: 37911 AF XY: 0.651 AC XY: 60275 AN XY: 92566

Gnomad AFR exome AF: 0.931

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.651

Gnomad SAS exome AF: 0.662

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.648

Gnomad OTH exome AF: 0.646

GnomAD4 exome AF: 0.667 AC: 940696 AN: 1410444 Hom.: 315683 Cov.: 51 AF XY: 0.666 AC XY: 464143 AN XY: 696810

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.579

Gnomad4 ASJ exome AF: 0.624

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.668

Gnomad4 FIN exome AF: 0.646

Gnomad4 NFE exome AF: 0.663

Gnomad4 OTH exome AF: 0.678

GnomAD4 genome AF: 0.727 AC: 110556 AN: 152096 Hom.: 41368 Cov.: 33 AF XY: 0.724 AC XY: 53857 AN XY: 74368

Gnomad4 AFR AF: 0.922

Gnomad4 AMR AF: 0.628

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.677

Gnomad4 SAS AF: 0.682

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.655

Gnomad4 OTH AF: 0.697

Alfa AF: 0.663 Hom.: 81779

Bravo AF: 0.732

TwinsUK AF: 0.662 AC: 2454

ALSPAC AF: 0.671 AC: 2587

ESP6500AA AF: 0.923 AC: 4032

ESP6500EA AF: 0.660 AC: 5655

ExAC AF: 0.593 AC: 66871

Asia WGS AF: 0.714 AC: 2485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Beaded hair Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.1
DANN	Benign	0.61
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00076	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.22
Sift	Benign	0.45	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.0	B
Vest4		0.069
MPC		0.084
ClinPred		0.0015	T
GERP RS		4.2
Varity_R		0.029
gMVP		0.13

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: rs2857671; hg19: chr12-52708420; COSMIC: COSV53338269;