17-40656410-C-G

Position:

• chr17-40656410-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152349.3(KRT222):​c.880G>C​(p.Ala294Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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: 1.29

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09594074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT222	NM_152349.3	c.880G>C	p.Ala294Pro	missense_variant	6/6	ENST00000394052.5	NP_689562.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT222	ENST00000394052.5	c.880G>C	p.Ala294Pro	missense_variant	6/6	1	NM_152349.3	ENSP00000377616.3
ENSG00000264058	ENST00000476049.1	n.880G>C		non_coding_transcript_exon_variant	6/13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.880G>C (p.A294P) alteration is located in exon 6 (coding exon 6) of the KRT222 gene. This alteration results from a G to C substitution at nucleotide position 880, causing the alanine (A) at amino acid position 294 to be replaced by a proline (P). 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	0.093
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.26
Sift	Uncertain	0.011	D
Sift4G	Benign	0.083	T
Polyphen		0.14	B
Vest4		0.16
MutPred		0.074		Gain of glycosylation at A294 (P = 0.018);
MVP		0.50
MPC		0.25
ClinPred		0.12	T
GERP RS		2.1
Varity_R		0.083
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38812662;