rs769548419

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_000223.4(KRT12):c.1442A>T(p.Glu481Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,461,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KRT12
NM_000223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Publications

0 publications found

Variant links:

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

KRT12 links:

ENSG00000265359 (HGNC:):

ENSG00000265359 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16945738).

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000753 (11/1461568) while in subpopulation AMR AF = 0.000246 (11/44724). AF 95% confidence interval is 0.000137. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT12	NM_000223.4 link	c.1442A>T	p.Glu481Val	missense_variant	Exon 8 of 8	ENST00000251643.5	NP_000214.1	Q99456
LOC105371777	XR_934754.3 link	n.63+10844T>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRT12	ENST00000251643.5 link	c.1442A>T	p.Glu481Val	missense_variant	Exon 8 of 8	1	NM_000223.4	ENSP00000251643.4	Q99456
ENSG00000265359	ENST00000579136.1 link	n.62-1382T>A		intron_variant	Intron 1 of 1	3
ENSG00000265359	ENST00000818906.1 link	n.61+10844T>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

250614

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727108

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111760

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1442A>T (p.E481V) alteration is located in exon 8 (coding exon 8) of the KRT12 gene. This alteration results from a A to T substitution at nucleotide position 1442, causing the glutamic acid (E) at amino acid position 481 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T

Eigen

Benign

-0.025

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.66

.;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.6

L;L

PhyloP100

4.2

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.7

.;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0010

.;D

Sift4G

Uncertain

0.013

.;D

Polyphen

0.14

B;B

Vest4

0.25

MutPred

0.46

Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);

MVP

0.57

MPC

.;8.38689937476E-4

ClinPred

0.33

GERP RS

5.7

Varity_R

0.33

gMVP

0.67

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

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rs769548419

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over