chr17-40866792-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000223.4(KRT12):​c.395T>C​(p.Leu132Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L132V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KRT12
NM_000223.4 missense

Scores

16
2
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.32
Variant links:
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_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 17-40866792-A-G is Pathogenic according to our data. Variant chr17-40866792-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 254686.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-40866792-A-G is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRT12NM_000223.4 linkuse as main transcriptc.395T>C p.Leu132Pro missense_variant 1/8 ENST00000251643.5 NP_000214.1
LOC105371777XR_934754.3 linkuse as main transcriptn.63+15932A>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRT12ENST00000251643.5 linkuse as main transcriptc.395T>C p.Leu132Pro missense_variant 1/81 NM_000223.4 ENSP00000251643 P1
KRT12ENST00000647902.1 linkuse as main transcriptc.287T>C p.Leu96Pro missense_variant 2/4 ENSP00000497770

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Corneal dystrophy, Meesmann, 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 04, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.96
D;D;.
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
.;D;T
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.5
H;H;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-6.4
.;D;.
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
.;D;.
Sift4G
Pathogenic
0.0
.;D;.
Polyphen
1.0
D;D;.
Vest4
0.99
MutPred
0.96
Gain of disorder (P = 0.0444);Gain of disorder (P = 0.0444);.;
MVP
0.99
MPC
0.86
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.97
gMVP
1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886038212; hg19: chr17-39023044; API