17-40863770-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000223.4(KRT12):c.902T>C(p.Met301Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,613,058 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.25

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]

LOC105371777 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056326628).
• BP6: Variant 17-40863770-A-G is Benign according to our data. Variant chr17-40863770-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 723635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (250/152238) while in subpopulation NFE AF= 0.00293 (199/67998). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 119 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT12	NM_000223.4	c.902T>C	p.Met301Thr	missense_variant	4/8	ENST00000251643.5
LOC105371777	XR_934754.3	n.63+12910A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT12	ENST00000251643.5	c.902T>C	p.Met301Thr	missense_variant	4/8	1	NM_000223.4	P1
KRT12	ENST00000648126.1	n.618T>C		non_coding_transcript_exon_variant	2/2
KRT12	ENST00000650597.1	n.373T>C		non_coding_transcript_exon_variant	4/6
KRT12	ENST00000648535.1			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00191 AC: 480 AN: 251370 Hom.: 3 AF XY: 0.00196 AC XY: 266 AN XY: 135892

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00283 AC: 4130 AN: 1460820 Hom.: 11 Cov.: 34 AF XY: 0.00275 AC XY: 1996 AN XY: 726686

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00260

Gnomad4 NFE exome AF: 0.00342

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74436

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00227 Hom.: 2

Bravo AF: 0.00161

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00235 AC: 285

EpiCase AF: 0.00229

EpiControl AF: 0.00237

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	KRT12: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 14, 2018	- -

KRT12-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.056	T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.57	T
Polyphen		0.98	D;D
Vest4		0.85
MVP		0.98
MPC		0.32
ClinPred		0.068	T
GERP RS		5.6
Varity_R		0.79
gMVP		0.88

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: rs139647784; hg19: chr17-39020022; COSMIC: COSV52431921; COSMIC: COSV52431921;