Variant 17-40863324-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000223.4(KRT12):c.1115C>A(p.Ser372Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

KRT12
NM_000223.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

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 links:

LOC105371777 (HGNC:):

LOC105371777 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000118 (18/152390) while in subpopulation AFR AF= 0.000409 (17/41602). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT12	NM_000223.4 link	c.1115C>A	p.Ser372Tyr	missense_variant	6/8	ENST00000251643.5	NP_000214.1	Q99456
LOC105371777	XR_934754.3 link	n.63+12464G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRT12	ENST00000251643.5 link	c.1115C>A	p.Ser372Tyr	missense_variant	6/8	1	NM_000223.4	ENSP00000251643.4	Q99456
KRT12	ENST00000648535.1 link	n.407C>A		non_coding_transcript_exon_variant	1/2
KRT12	ENST00000650597.1 link	n.586C>A		splice_region_variant, non_coding_transcript_exon_variant	6/6
ENSG00000265359	ENST00000579136.1 link	n.*42G>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247592

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134620

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000116

AC:

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000118

AC:

AN:

152390

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2024

The c.1115C>A (p.S372Y) alteration is located in exon 6 (coding exon 6) of the KRT12 gene. This alteration results from a C to A substitution at nucleotide position 1115, causing the serine (S) at amino acid position 372 to be replaced by a tyrosine (Y). 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

0.33

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.3

.;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0010

.;D

Polyphen

0.99

D;D

Vest4

0.40

MutPred

0.59

Loss of disorder (P = 0.0187);Loss of disorder (P = 0.0187);

MVP

0.96

MPC

2.3

ClinPred

0.98

GERP RS

5.0

Varity_R

0.91

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over