17-40861722-T-C

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.1424A>G(p.Gln475Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,613,904 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.29

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0133211315).
• BP6: Variant 17-40861722-T-C is Benign according to our data. Variant chr17-40861722-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2647749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40861722-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000952 (145/152354) while in subpopulation NFE AF= 0.00157 (107/68036). AF 95% confidence interval is 0.00133. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 144 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT12	NM_000223.4	c.1424A>G	p.Gln475Arg	missense_variant	8/8	ENST00000251643.5
LOC105371777	XR_934754.3	n.63+10862T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT12	ENST00000251643.5	c.1424A>G	p.Gln475Arg	missense_variant	8/8	1	NM_000223.4	P1
	ENST00000579136.1	n.62-1364T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000946 AC: 144 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00116 AC: 290 AN: 250234 Hom.: 1 AF XY: 0.00126 AC XY: 170 AN XY: 135424

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00153 AC: 2230 AN: 1461550 Hom.: 5 Cov.: 29 AF XY: 0.00152 AC XY: 1102 AN XY: 727102

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00341

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00191

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000952 AC: 145 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74520

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00113 AC: 137

Asia WGS AF: 0.000866 AC: 3 AN: 3478

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	Invitae	Nov 02, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	KRT12: BP4 -

KRT12-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 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	Benign	0.14
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.75	D
PrimateAI	Benign	0.34	T
Polyphen		0.36	B;B
Vest4		0.20
MVP		0.53
MPC		0.0013
ClinPred		0.061	T
GERP RS		4.6
Varity_R		0.22
gMVP		0.63

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: rs150149178; hg19: chr17-39017974; COSMIC: COSV105091260;