17-40863210-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000223.4(KRT12):c.1229T>G(p.Val410Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,614,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: KRT12 NM_000223.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.160

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004383743).
• BP6: Variant 17-40863210-A-C is Benign according to our data. Variant chr17-40863210-A-C is described in ClinVar as [Benign]. Clinvar id is 2716869.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000322 (49/152356) while in subpopulation EAS AF= 0.0056 (29/5180). AF 95% confidence interval is 0.004. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT12	NM_000223.4	c.1229T>G	p.Val410Gly	missense_variant	6/8	ENST00000251643.5
LOC105371777	XR_934754.3	n.63+12350A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT12	ENST00000251643.5	c.1229T>G	p.Val410Gly	missense_variant	6/8	1	NM_000223.4	P1
	ENST00000579136.1	n.186A>C		non_coding_transcript_exon_variant	2/2	3
KRT12	ENST00000648535.1	n.521T>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000530 AC: 132 AN: 249266 Hom.: 0 AF XY: 0.000547 AC XY: 74 AN XY: 135220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00534

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000188 AC: 275 AN: 1461698 Hom.: 1 Cov.: 34 AF XY: 0.000204 AC XY: 148 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00408

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000429 AC XY: 32 AN XY: 74510

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000320 Hom.: 0

Bravo AF: 0.000246

ExAC AF: 0.000585 AC: 71

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	14
Dann	Benign	0.64
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.63	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
Polyphen		0.0050	B;B
Vest4		0.15
MVP		0.72
MPC		1.2
ClinPred		0.0069	T
GERP RS		0.71
Varity_R		0.077
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs202225978; hg19: chr17-39019462;