rs142750223

chr17-41611714-G-Achr17-41611714-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005557.4(KRT16):c.539C>T(p.Ala180Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,609,484 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (19 hom.)
• Consequence: KRT16 NM_005557.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.566

Genes affected

KRT16 (HGNC:6423): (keratin 16) The protein encoded by this gene is a member of the keratin gene family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. Most of the type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains and are clustered in a region of chromosome 17q12-q21. This keratin has been coexpressed with keratin 14 in a number of epithelial tissues, including esophagus, tongue, and hair follicles. Mutations in this gene are associated with type 1 pachyonychia congenita, non-epidermolytic palmoplantar keratoderma and unilateral palmoplantar verrucous nevus. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008734137).
• BP6: Variant 17-41611714-G-A is Benign according to our data. Variant chr17-41611714-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 587419.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00131 (200/152324) while in subpopulation SAS AF= 0.00787 (38/4830). AF 95% confidence interval is 0.00589. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT16	NM_005557.4	c.539C>T	p.Ala180Val	missense_variant	2/8	ENST00000301653.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT16	ENST00000301653.9	c.539C>T	p.Ala180Val	missense_variant	2/8	1	NM_005557.4	P1
KRT16	ENST00000593067.1	c.-176C>T		5_prime_UTR_variant	3/7	3

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00241 AC: 579 AN: 240480 Hom.: 4 AF XY: 0.00287 AC XY: 372 AN XY: 129706

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.00876

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00157 AC: 2289 AN: 1457160 Hom.: 19 Cov.: 31 AF XY: 0.00183 AC XY: 1328 AN XY: 724646

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.00147

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00878

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000784

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00131 AC: 200 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74498

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00201 Hom.: 0

Bravo AF: 0.00163

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.00217 AC: 264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pachyonychia congenita 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Palmoplantar keratoderma, epidermolytic Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Benign	0.91
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		0.094	B
Vest4		0.20
MVP		0.37
MPC		0.32
ClinPred		0.0060	T
GERP RS		-7.8
Varity_R		0.068
gMVP		0.40

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: rs142750223; hg19: chr17-39767966;