17-40876456-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_019010.3(KRT20):ā€‹c.1180A>Gā€‹(p.Ile394Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

KRT20
NM_019010.3 missense, splice_region

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.94
Variant links:
Genes affected
KRT20 (HGNC:20412): (keratin 20) The protein encoded by this gene is a member of the keratin family. The keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into cytokeratins and hair keratins. The type I cytokeratins consist of acidic proteins which are arranged in pairs of heterotypic keratin chains. This cytokeratin is a major cellular protein of mature enterocytes and goblet cells and is specifically expressed in the gastric and intestinal mucosa. The type I cytokeratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.026715428).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRT20NM_019010.3 linkuse as main transcriptc.1180A>G p.Ile394Val missense_variant, splice_region_variant 8/8 ENST00000167588.4 NP_061883.1
LOC105371777XR_934754.3 linkuse as main transcriptn.63+25596T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRT20ENST00000167588.4 linkuse as main transcriptc.1180A>G p.Ile394Val missense_variant, splice_region_variant 8/81 NM_019010.3 ENSP00000167588 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.95e-7
AC:
1
AN:
1439836
Hom.:
0
Cov.:
27
AF XY:
0.00000139
AC XY:
1
AN XY:
717752
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.15e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 GeneticsFeb 28, 2023The c.1180A>G (p.I394V) alteration is located in exon 8 (coding exon 8) of the KRT20 gene. This alteration results from a A to G substitution at nucleotide position 1180, causing the isoleucine (I) at amino acid position 394 to be replaced by a valine (V). 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
0.065
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
0.0080
DANN
Benign
0.43
DEOGEN2
Benign
0.067
T
Eigen
Benign
-1.6
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.014
N
LIST_S2
Benign
0.11
T
M_CAP
Benign
0.0095
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-0.90
T
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
0.24
N
REVEL
Benign
0.20
Sift
Benign
0.52
T
Sift4G
Benign
0.43
T
Polyphen
0.0010
B
Vest4
0.030
MutPred
0.24
Gain of methylation at K395 (P = 0.0829);
MVP
0.42
MPC
0.24
ClinPred
0.035
T
GERP RS
-10
Varity_R
0.024
gMVP
0.077

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: chr17-39032708; API