rs58410481

Variant names:

• chr17-40866784-T-C
• rs58410481
• NM_000223.4:c.403A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R135S) has been classified as Uncertain significance.

• 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
• Publications: 11 publications found

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]

KRT12 Gene-Disease associations (from GenCC):

• corneal dystrophy, Meesmann, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Meesmann corneal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000265359 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000223.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40866783-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7924.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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 VariationId is 7923.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT12	NM_000223.4	c.403A>G	p.Arg135Gly	missense_variant	Exon 1 of 8	ENST00000251643.5	NP_000214.1
LOC105371777	XR_934754.3	n.63+15924T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT12	ENST00000251643.5	c.403A>G	p.Arg135Gly	missense_variant	Exon 1 of 8	1	NM_000223.4	ENSP00000251643.4
KRT12	ENST00000647902.1	c.295A>G	p.Arg99Gly	missense_variant	Exon 2 of 4			ENSP00000497770.1
ENSG00000265359	ENST00000818906.1	n.62-10934T>C		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Corneal dystrophy, Meesmann, 1 Pathogenic:1

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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;.
PhyloP100		5.0
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
PromoterAI		0.017	Neutral
Varity_R		0.92
gMVP		0.97
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs58410481; hg19: chr17-39023036;