chr12-52317765-G-T

Variant names:

• chr12-52317765-G-T
• rs2857667
• NM_002282.3:c.666C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_002282.3(KRT83):​c.666C>A​(p.Cys222*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 1,613,622 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C222C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0067 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0089 (82 hom.)
• Consequence: KRT83 NM_002282.3 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.996
• Publications: 18 publications found

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]

KRT83 Gene-Disease associations (from GenCC):

• monilethrix

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• erythrokeratodermia variabilis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KRT83-AS1 (HGNC:58282):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 12-52317765-G-T is Benign according to our data. Variant chr12-52317765-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1013 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002282.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT83	NM_002282.3	MANE Select	c.666C>A	p.Cys222*	stop_gained	Exon 4 of 9	NP_002273.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT83	ENST00000293670.3	TSL:1 MANE Select	c.666C>A	p.Cys222*	stop_gained	Exon 4 of 9	ENSP00000293670.3
	KRT83-AS1	ENST00000740301.1		n.507-4937G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1013 AN: 151924 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00545 AC: 1371 AN: 251448 AF XY: 0.00542

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00536

Gnomad NFE exome AF: 0.00935

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00889 AC: 12989 AN: 1461580 Hom.: 82 Cov.: 55 AF XY: 0.00866 AC XY: 6297 AN XY: 727090

African (AFR) AF: 0.00158 AC: 53 AN: 33470

American (AMR) AF: 0.00159 AC: 71 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00363 AC: 95 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86246

European-Finnish (FIN) AF: 0.00513 AC: 274 AN: 53420

Middle Eastern (MID) AF: 0.00142 AC: 8 AN: 5624

European-Non Finnish (NFE) AF: 0.0107 AC: 11847 AN: 1111896

Other (OTH) AF: 0.00923 AC: 557 AN: 60364

GnomAD4 genome AF: 0.00666 AC: 1013 AN: 152042 Hom.: 6 Cov.: 31 AF XY: 0.00612 AC XY: 455 AN XY: 74310

African (AFR) AF: 0.00149 AC: 62 AN: 41492

American (AMR) AF: 0.00379 AC: 58 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00376 AC: 13 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.00482 AC: 51 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 782 AN: 67954

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00959 Hom.: 1229

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.00882 AC: 34

ExAC AF: 0.00516 AC: 627

EpiCase AF: 0.00911

EpiControl AF: 0.00812

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	KRT83-related disorder (1)
-	-	1	Monilethrix (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.071
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.12	N
PhyloP100		-1.0
Vest4		0.13
GERP RS		-2.6
Mutation Taster		=175/25	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs2857667; hg19: chr12-52711549; COSMIC: COSV53338788;