Genetic Variant KRT222:p.Ser181Pro (chr17-40657470-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_152349.3(KRT222):c.541T>C(p.Ser181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,600,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

KRT222
NM_152349.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09

Publications

0 publications found

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]

KRT222 links:

ENSG00000264058 (HGNC:):

ENSG00000264058 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.541T>C	p.Ser181Pro	missense_variant	Exon 5 of 6	ENST00000394052.5	NP_689562.1	Q8N1A0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT222	ENST00000394052.5 link	c.541T>C	p.Ser181Pro	missense_variant	Exon 5 of 6	1	NM_152349.3	ENSP00000377616.3		Q8N1A0-1
ENSG00000264058	ENST00000476049.1 link	n.541T>C		non_coding_transcript_exon_variant	Exon 5 of 13	5		ENSP00000463483.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.00000821

AC:

AN:

243696

AF XY:

0.00000758

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1448474

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

720836

show subpopulations

African (AFR)

AF:

0.0000907

AC:

AN:

33078

American (AMR)

AF:

0.00

AC:

AN:

43794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25930

East Asian (EAS)

AF:

0.00

AC:

AN:

39470

South Asian (SAS)

AF:

0.00

AC:

AN:

84910

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5118

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104008

Other (OTH)

AF:

0.0000167

AC:

AN:

59878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.541T>C (p.S181P) alteration is located in exon 5 (coding exon 5) of the KRT222 gene. This alteration results from a T to C substitution at nucleotide position 541, causing the serine (S) at amino acid position 181 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

0.079

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.057

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.63

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.90

PhyloP100

2.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.90

REVEL

Uncertain

0.39

Sift

Benign

0.049

Sift4G

Benign

0.18

Polyphen

0.88

Vest4

0.56

MutPred

0.53

Loss of catalytic residue at S181 (P = 0.0511);

MVP

0.86

MPC

0.44

ClinPred

0.20

GERP RS

5.2

Varity_R

0.28

gMVP

0.57

Mutation Taster

=73/27

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

17-40657470-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over