17-40866783-C-A

Variant names:

• chr17-40866783-C-A
• rs57218384
• NM_000223.4:c.404G>T

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.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. 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: 6.11
• Publications: 20 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 chr17-40866784-T-C is described in ClinVar as Pathogenic. ClinVar VariationId 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 VariationId is 7924.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000223.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT12	NM_000223.4	MANE Select	c.404G>T	p.Arg135Ile	missense	Exon 1 of 8	NP_000214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT12	ENST00000251643.5	TSL:1 MANE Select	c.404G>T	p.Arg135Ile	missense	Exon 1 of 8	ENSP00000251643.4
	KRT12	ENST00000647902.1		c.296G>T	p.Arg99Ile	missense	Exon 2 of 4	ENSP00000497770.1
	ENSG00000265359	ENST00000818906.1		n.62-10935C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Corneal dystrophy, Meesmann, 1 (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		6.1
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
Vest4		0.96
MutPred		0.98		Loss of disorder (P = 0.0157)
MVP		0.98
MPC		0.41
ClinPred		1.0	D
GERP RS		5.9
PromoterAI		-0.0060	Neutral
Varity_R		0.97
gMVP		0.95
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs57218384; hg19: chr17-39023035;