12-52488072-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005554.4(KRT6A):c.1456A>G(p.Ile486Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,778 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (34 hom.)
• Consequence: KRT6A NM_005554.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061956644).
• BP6: Variant 12-52488072-T-C is Benign according to our data. Variant chr12-52488072-T-C is described in ClinVar as [Benign]. Clinvar id is 1546327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1780/152222) while in subpopulation AFR AF= 0.0397 (1647/41534). AF 95% confidence interval is 0.0381. There are 43 homozygotes in gnomad4. There are 837 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1777 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT6A	NM_005554.4	c.1456A>G	p.Ile486Val	missense_variant	8/9	ENST00000330722.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT6A	ENST00000330722.7	c.1456A>G	p.Ile486Val	missense_variant	8/9	1	NM_005554.4	P1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1777 AN: 152104 Hom.: 43 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00713

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00318 AC: 800 AN: 251282 Hom.: 14 AF XY: 0.00236 AC XY: 321 AN XY: 135816

Gnomad AFR exome AF: 0.0400

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00122 AC: 1783 AN: 1461556 Hom.: 34 Cov.: 35 AF XY: 0.00106 AC XY: 773 AN XY: 727100

Gnomad4 AFR exome AF: 0.0397

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.00234

GnomAD4 genome AF: 0.0117 AC: 1780 AN: 152222 Hom.: 43 Cov.: 32 AF XY: 0.0112 AC XY: 837 AN XY: 74406

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00316 Hom.: 3

Bravo AF: 0.0138

ESP6500AA AF: 0.0379 AC: 167

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00413 AC: 502

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0062	T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.41
Sift	Benign	0.075	T
Sift4G	Benign	0.28	T
Polyphen		0.73	P
Vest4		0.18
MVP		0.79
MPC		0.30
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.092
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150913083; hg19: chr12-52881856; COSMIC: COSV58105442; COSMIC: COSV58105442;