17-40863150-C-G

Position:

• chr17-40863150-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000223.4(KRT12):​c.1289G>C​(p.Arg430Pro) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 4.05

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]

ENSG00000265359 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT12	NM_000223.4	c.1289G>C	p.Arg430Pro	missense_variant	6/8	ENST00000251643.5	NP_000214.1
LOC105371777	XR_934754.3	n.63+12290C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT12	ENST00000251643.5	c.1289G>C	p.Arg430Pro	missense_variant	6/8	1	NM_000223.4	ENSP00000251643.4
ENSG00000265359	ENST00000579136.1	n.126C>G		non_coding_transcript_exon_variant	2/2	3
KRT12	ENST00000648535.1	n.581G>C		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-6.0	.;D
REVEL	Pathogenic	0.93
Sift	Benign	0.064	.;T
Sift4G	Uncertain	0.0070	.;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.95		Loss of phosphorylation at T428 (P = 0.1329);Loss of phosphorylation at T428 (P = 0.1329);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		1.0

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: rs62635290; hg19: chr17-39019402;