chr12-52314493-G-A

Position:

• chr12-52314493-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.*138C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 813,116 control chromosomes in the GnomAD database, including 56,954 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12052 hom., cov: 34)
  • Exomes 𝑓: 0.36 (44902 hom.)
• Consequence: KRT83 NM_002282.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.23

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 (BayesDel_noAF=-0.71).
• BP6: Variant 12-52314493-G-A is Benign according to our data. Variant chr12-52314493-G-A is described in ClinVar as [Benign]. Clinvar id is 309490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT83	NM_002282.3	c.*138C>T		3_prime_UTR_variant	9/9	ENST00000293670.3	NP_002273.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT83	ENST00000293670	c.*138C>T		3_prime_UTR_variant	9/9	1	NM_002282.3	ENSP00000293670.3

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59793 AN: 152056 Hom.: 12034 Cov.: 34

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.334

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.363 AC: 239597 AN: 660946 Hom.: 44902 Cov.: 9 AF XY: 0.366 AC XY: 127172 AN XY: 347468

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.263

Gnomad4 ASJ exome AF: 0.310

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.415

Gnomad4 FIN exome AF: 0.328

Gnomad4 NFE exome AF: 0.376

Gnomad4 OTH exome AF: 0.368

GnomAD4 genome AF: 0.393 AC: 59845 AN: 152170 Hom.: 12052 Cov.: 34 AF XY: 0.390 AC XY: 28985 AN XY: 74396

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.333

Gnomad4 ASJ AF: 0.314

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.418

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.389

Gnomad4 OTH AF: 0.367

Alfa AF: 0.393 Hom.: 3513

Bravo AF: 0.394

Asia WGS AF: 0.326 AC: 1134 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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 13, 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
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.7
DANN	Benign	0.90

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: rs2857672; hg19: chr12-52708277; COSMIC: COSV53338255;