chr17-40863154-A-C

Variant names:

• chr17-40863154-A-C
• rs58162394
• NM_000223.4:c.1285T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000223.4(KRT12):​c.1285T>G​(p.Tyr429Asp) 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. Y429C) 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: 9.14
• Publications: 10 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-40863154-A-C is Pathogenic according to our data. Variant chr17-40863154-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 7925.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.1285T>G	p.Tyr429Asp	missense_variant	Exon 6 of 8	ENST00000251643.5	NP_000214.1
LOC105371777	XR_934754.3	n.63+12294A>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT12	ENST00000251643.5	c.1285T>G	p.Tyr429Asp	missense_variant	Exon 6 of 8	1	NM_000223.4	ENSP00000251643.4

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	0.90
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
PhyloP100		9.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-9.3	.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.97		Gain of disorder (P = 0.0036);Gain of disorder (P = 0.0036);
MVP		0.94
MPC		2.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.95
gMVP		1.0
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs58162394; hg19: chr17-39019406;