rs267607387

Positions:

• chr17-40866802-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000223.4(KRT12):​c.385A>G​(p.Met129Val) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 5.04

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 17-40866802-T-C is Pathogenic according to our data. Variant chr17-40866802-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40866802-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.385A>G	p.Met129Val	missense_variant	1/8	ENST00000251643.5	NP_000214.1
LOC105371777	XR_934754.3	n.63+15942T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT12	ENST00000251643.5	c.385A>G	p.Met129Val	missense_variant	1/8	1	NM_000223.4	ENSP00000251643.4
KRT12	ENST00000647902.1	c.277A>G	p.Met93Val	missense_variant	2/4			ENSP00000497770.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2024	Located in the highly conserved helix initiation motif of the alpha-helical rod domain, which is intolerant to change; variants in this motif interfere with proper keratin intermediate filament assembly and function, damaging the structural integrity of corneal epithelial cells, resulting in corneal dystrophy (PMID: 20577595, 26758872); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20577595, 26758872) -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D;T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.7	H;H;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	.;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0010	.;D;.
Polyphen		0.89	P;P;.
Vest4		0.82
MutPred		0.75		Loss of disorder (P = 0.1043);Loss of disorder (P = 0.1043);.;
MVP		0.95
MPC		0.67
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.89
gMVP		0.96

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

Other links and lift over

dbSNP: rs267607387; hg19: chr17-39023054;