17-40656433-G-A

Variant names:

• chr17-40656433-G-A
• rs1000127471
• NM_152349.3:c.857C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152349.3(KRT222):​c.857C>T​(p.Pro286Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KRT222 NM_152349.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29
• Publications: 0 publications found

Genes affected

KRT222 (HGNC:28695): (keratin 222) Predicted to enable structural molecule activity. Predicted to be located in intermediate filament. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000264058 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT222	NM_152349.3	c.857C>T	p.Pro286Leu	missense_variant	Exon 6 of 6	ENST00000394052.5	NP_689562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT222	ENST00000394052.5	c.857C>T	p.Pro286Leu	missense_variant	Exon 6 of 6	1	NM_152349.3	ENSP00000377616.3
ENSG00000264058	ENST00000476049.1	n.857C>T		non_coding_transcript_exon_variant	Exon 6 of 13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.857C>T (p.P286L) alteration is located in exon 6 (coding exon 6) of the KRT222 gene. This alteration results from a C to T substitution at nucleotide position 857, causing the proline (P) at amino acid position 286 to be replaced by a leucine (L). 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	Uncertain	0.52
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.1	L
PhyloP100		9.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.25		Loss of disorder (P = 0.0101);
MVP		0.91
MPC		0.42
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.46

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: rs1000127471; hg19: chr17-38812685;