17-40656541-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152349.3(KRT222):​c.749G>T​(p.Arg250Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KRT222
NM_152349.3 missense

Scores

9
5
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.747

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRT222NM_152349.3 linkc.749G>T p.Arg250Leu missense_variant 6/6 ENST00000394052.5 NP_689562.1 Q8N1A0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRT222ENST00000394052.5 linkc.749G>T p.Arg250Leu missense_variant 6/61 NM_152349.3 ENSP00000377616.3 Q8N1A0-1
ENSG00000264058ENST00000476049.1 linkn.749G>T non_coding_transcript_exon_variant 6/135 ENSP00000463483.1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152094
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00144
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251396
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1461428
Hom.:
0
Cov.:
30
AF XY:
0.0000151
AC XY:
11
AN XY:
727028
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000224
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:
0.00000630
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152094
Hom.:
0
Cov.:
31
AF XY:
0.000215
AC XY:
16
AN XY:
74294
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00144
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000956
Bravo
AF:
0.000166
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 01, 2024The c.749G>T (p.R250L) alteration is located in exon 6 (coding exon 6) of the KRT222 gene. This alteration results from a G to T substitution at nucleotide position 749, causing the arginine (R) at amino acid position 250 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
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.092
T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.063
D
MetaRNN
Pathogenic
0.75
D
MetaSVM
Uncertain
0.60
D
MutationAssessor
Benign
1.1
L
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-2.3
N
REVEL
Uncertain
0.64
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.82
MVP
0.93
MPC
0.81
ClinPred
0.93
D
GERP RS
5.9
Varity_R
0.29
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs139112704; hg19: chr17-38812793; COSMIC: COSV67499259; COSMIC: COSV67499259; API