chr12-52487760-G-C

Position:

• chr12-52487760-G-C

Variant summary

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

The NM_005554.4(KRT6A):​c.1655C>G​(p.Thr552Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,996 control chromosomes in the GnomAD database, including 2,793 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 0.082 (1312 hom., cov: 32)
  • Exomes 𝑓: 0.018 (1481 hom.)
• Consequence: KRT6A NM_005554.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0140

Genes affected

KRT6A (HGNC:6443): (keratin 6A) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. As many as six of this type II cytokeratin (KRT6) have been identified; the multiplicity of the genes is attributed to successive gene duplication events. The genes are expressed with family members KRT16 and/or KRT17 in the filiform papillae of the tongue, the stratified epithelial lining of oral mucosa and esophagus, the outer root sheath of hair follicles, and the glandular epithelia. This KRT6 gene in particular encodes the most abundant isoform. Mutations in these genes have been associated with pachyonychia congenita. In addition, peptides from the C-terminal region of the protein have antimicrobial activity against bacterial pathogens. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021026134).
• BP6: Variant 12-52487760-G-C is Benign according to our data. Variant chr12-52487760-G-C is described in ClinVar as [Benign]. Clinvar id is 1561393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT6A	NM_005554.4	c.1655C>G	p.Thr552Ser	missense_variant	9/9	ENST00000330722.7	NP_005545.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT6A	ENST00000330722.7	c.1655C>G	p.Thr552Ser	missense_variant	9/9	1	NM_005554.4	ENSP00000369317	P1

Frequencies

GnomAD3 genomes AF: 0.0814 AC: 12371 AN: 152054 Hom.: 1303 Cov.: 32

Gnomad AFR AF: 0.242

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.0755

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0487

Gnomad SAS AF: 0.0377

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00756

Gnomad OTH AF: 0.0645

GnomAD3 exomes AF: 0.0392 AC: 9854 AN: 251460 Hom.: 684 AF XY: 0.0331 AC XY: 4504 AN XY: 135910

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.0483

Gnomad SAS exome AF: 0.0336

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00777

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0181 AC: 26405 AN: 1461824 Hom.: 1481 Cov.: 35 AF XY: 0.0177 AC XY: 12849 AN XY: 727222

Gnomad4 AFR exome AF: 0.253

Gnomad4 AMR exome AF: 0.0813

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.0383

Gnomad4 SAS exome AF: 0.0331

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00681

Gnomad4 OTH exome AF: 0.0302

GnomAD4 genome AF: 0.0816 AC: 12417 AN: 152172 Hom.: 1312 Cov.: 32 AF XY: 0.0812 AC XY: 6043 AN XY: 74400

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.0756

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0486

Gnomad4 SAS AF: 0.0377

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00756

Gnomad4 OTH AF: 0.0629

Alfa AF: 0.0261 Hom.: 106

Bravo AF: 0.0939

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.236 AC: 1039

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.0412 AC: 5007

EpiCase AF: 0.0112

EpiControl AF: 0.00960

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.14
Sift	Benign	0.12	T
Sift4G	Benign	0.58	T
Polyphen		0.0030	B
Vest4		0.040
MutPred		0.31		Gain of catalytic residue at S555 (P = 9e-04);
MPC		0.25
ClinPred		0.0044	T
GERP RS		2.7
Varity_R		0.061
gMVP		0.24

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: rs11540301; hg19: chr12-52881544; COSMIC: COSV58106809; COSMIC: COSV58106809;