rs57218384

Positions:

• chr17-40866783-C-A
• chr17-40866783-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000251643.5(KRT12):​c.404G>T​(p.Arg135Ile) 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. R135G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT12 ENST00000251643.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 6.11

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 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000251643.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-40866783-C-A is Pathogenic according to our data. Variant chr17-40866783-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7924.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr17-40866783-C-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT12	NM_000223.4	c.404G>T	p.Arg135Ile	missense_variant	1/8	ENST00000251643.5	NP_000214.1
LOC105371777	XR_934754.3	n.63+15923C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT12	ENST00000251643.5	c.404G>T	p.Arg135Ile	missense_variant	1/8	1	NM_000223.4	ENSP00000251643	P1
KRT12	ENST00000647902.1	c.296G>T	p.Arg99Ile	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 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	0.87
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-7.3	.;D;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0010	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.96
MutPred		0.98		Loss of disorder (P = 0.0157);Loss of disorder (P = 0.0157);.;
MVP		0.98
MPC		0.41
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs57218384; hg19: chr17-39023035;