17-41610332-G-A

Position:

• chr17-41610332-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005557.4(KRT16):​c.1279C>T​(p.His427Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KRT16 NM_005557.4 missense, splice_region
• Scores: Splicing: ADA: 0.001081
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.72

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3231702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT16	NM_005557.4	c.1279C>T	p.His427Tyr	missense_variant, splice_region_variant	6/8	ENST00000301653.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT16	ENST00000301653.9	c.1279C>T	p.His427Tyr	missense_variant, splice_region_variant	6/8	1	NM_005557.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460752 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726676

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2022

The c.1279C>T (p.H427Y) alteration is located in exon 6 (coding exon 6) of the KRT16 gene. This alteration results from a C to T substitution at nucleotide position 1279, causing the histidine (H) at amino acid position 427 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.12	T
Sift4G	Benign	0.14	T
Polyphen		0.11	B
Vest4		0.44
MutPred		0.53		Gain of phosphorylation at H427 (P = 0.0085);
MVP		0.58
MPC		1.1
ClinPred		0.91	D
GERP RS		3.0
Varity_R		0.21
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.026
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: rs1908142710; hg19: chr17-39766584;