12-52469307-G-T

Variant names:

• chr12-52469307-G-T
• rs35481773
• NM_173086.5:c.1460-10C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173086.5(KRT6C):​c.1460-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 1,613,608 control chromosomes in the GnomAD database, including 40,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4295 hom., cov: 33)
  • Exomes 𝑓: 0.22 (35716 hom.)
• Consequence: KRT6C NM_173086.5 intron
• Scores: Splicing: ADA: 0.003670
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.986
• Publications: 5 publications found

Genes affected

KRT6C (HGNC:20406): (keratin 6C) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. The type II keratins are clustered in a region of chromosome 12q13. [provided by RefSeq, Jul 2009]

KRT6C Gene-Disease associations (from GenCC):

• palmoplantar keratoderma, nonepidermolytic, focal or diffuse

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-52469307-G-T is Benign according to our data. Variant chr12-52469307-G-T is described in ClinVar as Benign. ClinVar VariationId is 1300091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173086.5. 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
	KRT6C	NM_173086.5	MANE Select	c.1460-10C>A		intron	N/A	NP_775109.2	P48668

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6C	ENST00000252250.7	TSL:1 MANE Select	c.1460-10C>A		intron	N/A	ENSP00000252250.6	P48668

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35688 AN: 152026 Hom.: 4283 Cov.: 33

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.262

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.232 AC: 58207 AN: 250594 AF XY: 0.228

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.328

Gnomad ASJ exome AF: 0.242

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.215

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.218 AC: 318726 AN: 1461464 Hom.: 35716 Cov.: 75 AF XY: 0.217 AC XY: 157695 AN XY: 727008

African (AFR) AF: 0.224 AC: 7508 AN: 33476

American (AMR) AF: 0.324 AC: 14452 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 6179 AN: 26128

East Asian (EAS) AF: 0.135 AC: 5364 AN: 39692

South Asian (SAS) AF: 0.206 AC: 17743 AN: 86242

European-Finnish (FIN) AF: 0.260 AC: 13882 AN: 53404

Middle Eastern (MID) AF: 0.197 AC: 1135 AN: 5766

European-Non Finnish (NFE) AF: 0.215 AC: 239218 AN: 1111746

Other (OTH) AF: 0.219 AC: 13245 AN: 60374

GnomAD4 genome AF: 0.235 AC: 35715 AN: 152144 Hom.: 4295 Cov.: 33 AF XY: 0.238 AC XY: 17717 AN XY: 74358

African (AFR) AF: 0.229 AC: 9489 AN: 41484

American (AMR) AF: 0.326 AC: 4980 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3468

East Asian (EAS) AF: 0.148 AC: 766 AN: 5172

South Asian (SAS) AF: 0.215 AC: 1038 AN: 4828

European-Finnish (FIN) AF: 0.262 AC: 2777 AN: 10596

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14920 AN: 67986

Other (OTH) AF: 0.257 AC: 542 AN: 2112

Alfa AF: 0.220 Hom.: 1096

Bravo AF: 0.238

Asia WGS AF: 0.225 AC: 785 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	KRT6C-related disorder (1)
-	-	1	Palmoplantar keratoderma, nonepidermolytic, focal or diffuse (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.83
DANN	Benign	0.86
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
dbscSNV1_RF	Benign	0.17
SpliceAI score (max)		0.040		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: rs35481773; hg19: chr12-52863091; COSMIC: COSV52876918; COSMIC: COSV52876918;