17-40863163-T-C

Variant summary

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

The NM_000223.4(KRT12):c.1276A>G(p.Ile426Val) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I426S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.12

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]

(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, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT12	NM_000223.4	c.1276A>G	p.Ile426Val	missense_variant	6/8	ENST00000251643.5
LOC105371777	XR_934754.3	n.63+12303T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT12	ENST00000251643.5	c.1276A>G	p.Ile426Val	missense_variant	6/8	1	NM_000223.4	P1
	ENST00000579136.1	n.139T>C		non_coding_transcript_exon_variant	2/2	3
KRT12	ENST00000648535.1	n.568A>G		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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.48	T
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.97		Gain of disorder (P = 0.0517);Gain of disorder (P = 0.0517);
MVP		0.87
MPC		1.9
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs59465138; hg19: chr17-39019415;