rs58410481

Positions:

• chr17-40866784-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000223.4(KRT12):​c.403A>G​(p.Arg135Gly) variant causes a missense change. 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.97

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]

LOC105371777 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-40866784-T-C is Pathogenic according to our data. Variant chr17-40866784-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7923.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-40866784-T-C is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT12	NM_000223.4	c.403A>G	p.Arg135Gly	missense_variant	1/8	ENST00000251643.5	NP_000214.1
LOC105371777	XR_934754.3	n.63+15924T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT12	ENST00000251643.5	c.403A>G	p.Arg135Gly	missense_variant	1/8	1	NM_000223.4	ENSP00000251643.4
KRT12	ENST00000647902.1	c.295A>G	p.Arg99Gly	missense_variant	2/4			ENSP00000497770.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Corneal dystrophy, Meesmann, 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.4	.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;.
Sift4G	Uncertain	0.0020	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.99		Loss of stability (P = 0.0141);Loss of stability (P = 0.0141);.;
MVP		0.96
MPC		0.73
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.92
gMVP		0.97

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

Other links and lift over

dbSNP: rs58410481; hg19: chr17-39023036;