17-40863756-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2
The NM_000223.4(KRT12):c.916G>A(p.Glu306Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,330 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 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
KRT12
NM_000223.4 missense
NM_000223.4 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 6.08
Genes affected
KRT12 (HGNC:6414): (keratin 12) KRT12 encodes the type I intermediate filament chain keratin 12, expressed in corneal epithelia. Mutations in this gene lead to Meesmann corneal dystrophy. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.939
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000788 (12/152308) while in subpopulation AFR AF= 0.000289 (12/41566). AF 95% confidence interval is 0.000166. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 12 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT12 | NM_000223.4 | c.916G>A | p.Glu306Lys | missense_variant | 4/8 | ENST00000251643.5 | |
LOC105371777 | XR_934754.3 | n.63+12896C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT12 | ENST00000251643.5 | c.916G>A | p.Glu306Lys | missense_variant | 4/8 | 1 | NM_000223.4 | P1 | |
KRT12 | ENST00000648126.1 | n.632G>A | non_coding_transcript_exon_variant | 2/2 | |||||
KRT12 | ENST00000650597.1 | n.387G>A | non_coding_transcript_exon_variant | 4/6 | |||||
KRT12 | ENST00000648535.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251422Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2023 | The c.916G>A (p.E306K) alteration is located in exon 4 (coding exon 4) of the KRT12 gene. This alteration results from a G to A substitution at nucleotide position 916, causing the glutamic acid (E) at amino acid position 306 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
Polyphen
D;D
Vest4
0.95
MVP
0.98
MPC
0.71
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at