12-52173620-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_182507.3(KRT80):​c.811G>A​(p.Glu271Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,612,742 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00039 ( 2 hom. )

Consequence

KRT80
NM_182507.3 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.29
Variant links:
Genes affected
KRT80 (HGNC:27056): (keratin 80) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. This gene's expression profile shows that it encodes a type II epithelial keratin, although structurally the encoded protein is more like a type II hair keratin. This protein is involved in cell differentiation, localizing near desmosomal plaques in earlier stages of differentiation but then dispersing throughout the cytoplasm in terminally differentiating cells. The type II keratins are clustered in a region of chromosome 12q13. Two transcript variants encoding two different fully functional isoforms have been found for this gene.[provided by RefSeq, Oct 2010]
LINC00592 (HGNC:27474): (long intergenic non-protein coding RNA 592)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.22593415).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT80NM_182507.3 linkc.811G>A p.Glu271Lys missense_variant Exon 5 of 9 ENST00000394815.3 NP_872313.2 Q6KB66-1
KRT80NM_001081492.2 linkc.811G>A p.Glu271Lys missense_variant Exon 5 of 9 NP_001074961.1 Q6KB66-2
KRT80XM_005268676.4 linkc.916G>A p.Glu306Lys missense_variant Exon 3 of 7 XP_005268733.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT80ENST00000394815.3 linkc.811G>A p.Glu271Lys missense_variant Exon 5 of 9 1 NM_182507.3 ENSP00000378292.2 Q6KB66-1
KRT80ENST00000313234.9 linkc.811G>A p.Glu271Lys missense_variant Exon 5 of 9 1 ENSP00000369361.2 Q6KB66-2
KRT80ENST00000466011.1 linkn.967G>A non_coding_transcript_exon_variant Exon 3 of 7 2
LINC00592ENST00000640420.1 linkn.413+8669C>T intron_variant Intron 2 of 2 5

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152144
Hom.:
0
Cov.:
33
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:
0.000338
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000136
AC:
34
AN:
249580
Hom.:
0
AF XY:
0.000126
AC XY:
17
AN XY:
135098
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000239
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000392
AC:
573
AN:
1460480
Hom.:
2
Cov.:
32
AF XY:
0.000367
AC XY:
267
AN XY:
726646
show subpopulations
Gnomad4 AFR exome
AF:
0.000179
Gnomad4 AMR exome
AF:
0.0000447
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:
0.000497
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.000177
AC:
27
AN:
152262
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000270
Hom.:
0
Bravo
AF:
0.000174
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000349
AC:
3
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.000327
EpiControl
AF:
0.000296

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.811G>A (p.E271K) alteration is located in exon 5 (coding exon 5) of the KRT80 gene. This alteration results from a G to A substitution at nucleotide position 811, causing the glutamic acid (E) at amino acid position 271 to be replaced by a lysine (K). 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
Benign
-0.088
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
.;D
Eigen
Benign
0.10
Eigen_PC
Benign
0.042
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.038
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Uncertain
0.63
D
MutationAssessor
Uncertain
2.7
M;M
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Uncertain
0.50
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.0050
D;D
Polyphen
0.43
B;P
Vest4
0.46
MVP
0.60
MPC
0.16
ClinPred
0.27
T
GERP RS
2.4
Varity_R
0.28
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs148980872; hg19: chr12-52567404; COSMIC: COSV57548637; API