chr17-40863123-C-T
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000223.4(KRT12):c.1316G>A(p.Gly439Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )
Consequence
KRT12
NM_000223.4 missense, splice_region
NM_000223.4 missense, splice_region
Scores
7
7
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 2.77
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 -4 ACMG points.
BS2
High AC in GnomAdExome4 at 37 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT12 | NM_000223.4 | c.1316G>A | p.Gly439Asp | missense_variant, splice_region_variant | 6/8 | ENST00000251643.5 | |
LOC105371777 | XR_934754.3 | n.63+12263C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT12 | ENST00000251643.5 | c.1316G>A | p.Gly439Asp | missense_variant, splice_region_variant | 6/8 | 1 | NM_000223.4 | P1 | |
ENST00000579136.1 | n.99C>T | non_coding_transcript_exon_variant | 2/2 | 3 | |||||
KRT12 | ENST00000648535.1 | n.608G>A | splice_region_variant, non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249878Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135414
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GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461664Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15AN XY: 727152
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152246Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74384
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Benign
T
Polyphen
D;D
Vest4
0.59
MutPred
Gain of solvent accessibility (P = 0.2192);Gain of solvent accessibility (P = 0.2192);
MVP
0.67
MPC
2.3
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at