chr17-41612321-T-C

Variant names:

• chr17-41612321-T-C
• rs121912477
• NM_005557.4:c.368A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005557.4(KRT16):​c.368A>G​(p.Asn123Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT16 NM_005557.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.15
• Publications: 1 publications found

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]

KRT16 Gene-Disease associations (from GenCC):

• pachyonychia congenita 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• palmoplantar keratoderma, nonepidermolytic, focal 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp
• isolated focal non-epidermolytic palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pachyonychia congenita

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005557.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT16	NM_005557.4	c.368A>G	p.Asn123Ser	missense_variant	Exon 1 of 8	ENST00000301653.9	NP_005548.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT16	ENST00000301653.9	c.368A>G	p.Asn123Ser	missense_variant	Exon 1 of 8	1	NM_005557.4	ENSP00000301653.3
KRT16	ENST00000588319.1	n.445A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6
KRT16	ENST00000593067.1	c.-312-35A>G		intron_variant	Intron 1 of 6	3		ENSP00000467124.1
KRT16	ENST00000590990.1	c.*222A>G		downstream_gene_variant		4		ENSP00000467105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	0.062
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.0034	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.39
Sift	Benign	0.074	T
Sift4G	Uncertain	0.027	D
Polyphen		0.57	P
Vest4		0.47
MutPred		0.56		Gain of disorder (P = 0.0899);
MVP		0.79
MPC		0.86
ClinPred		0.99	D
GERP RS		3.4
PromoterAI		-0.014	Neutral
Varity_R		0.27
gMVP		0.92

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

Other links and lift over

dbSNP: rs121912477; hg19: chr17-39768573;