chr17-40863707-T-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_000223.4(KRT12):c.965A>G(p.Glu322Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000064 ( 0 hom. )
Consequence
KRT12
NM_000223.4 missense
NM_000223.4 missense
Scores
6
8
Clinical Significance
Conservation
PhyloP100: 0.646
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 -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.406667).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000394 (6/152222) while in subpopulation NFE AF= 0.0000882 (6/68032). AF 95% confidence interval is 0.0000376. There are 0 homozygotes in gnomad4. There are 1 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 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRT12 | NM_000223.4 | c.965A>G | p.Glu322Gly | missense_variant | 4/8 | ENST00000251643.5 | |
LOC105371777 | XR_934754.3 | n.63+12847T>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRT12 | ENST00000251643.5 | c.965A>G | p.Glu322Gly | missense_variant | 4/8 | 1 | NM_000223.4 | P1 | |
KRT12 | ENST00000648535.1 | n.24A>G | non_coding_transcript_exon_variant | 1/2 | |||||
KRT12 | ENST00000650597.1 | n.436A>G | non_coding_transcript_exon_variant | 4/6 | |||||
KRT12 | ENST00000648126.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 32
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?
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251334Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135894
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GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461740Hom.: 0 Cov.: 34 AF XY: 0.0000509 AC XY: 37AN XY: 727164
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74374
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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 | Sep 20, 2023 | The c.965A>G (p.E322G) alteration is located in exon 4 (coding exon 4) of the KRT12 gene. This alteration results from a A to G substitution at nucleotide position 965, causing the glutamic acid (E) at amino acid position 322 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D
PrimateAI
Benign
T
Polyphen
D;D
Vest4
0.52
MVP
0.94
MPC
0.71
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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