12-52790941-G-A

Variant names:

• chr12-52790941-G-A
• rs12312467
• NM_057088.3:c.1536-69C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_057088.3(KRT3):​c.1536-69C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,449,242 control chromosomes in the GnomAD database, including 8,611 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.079 (1304 hom., cov: 33)
  • Exomes 𝑓: 0.058 (7307 hom.)
• Consequence: KRT3 NM_057088.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.491
• Publications: 5 publications found

Genes affected

KRT3 (HGNC:6440): (keratin 3) The protein encoded by this gene is a member of the keratin gene family. The type II cytokeratins consist of basic or neutral proteins which are arranged in pairs of heterotypic keratin chains coexpressed during differentiation of simple and stratified epithelial tissues. This type II cytokeratin is specifically expressed in the corneal epithelium with family member KRT12 and mutations in these genes have been associated with Meesmann's Corneal Dystrophy. The type II cytokeratins are clustered in a region of chromosome 12q12-q13. [provided by RefSeq, Jul 2008]

KRT3 Gene-Disease associations (from GenCC):

• corneal dystrophy, Meesmann, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• corneal dystrophy, Meesmann, 2

  Inheritance: AD Classification: STRONG Submitted by: G2P
• Meesmann corneal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057088.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT3	NM_057088.3	MANE Select	c.1536-69C>T		intron	N/A	NP_476429.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT3	ENST00000417996.2	TSL:1 MANE Select	c.1536-69C>T		intron	N/A	ENSP00000413479.2

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11976 AN: 152110 Hom.: 1290 Cov.: 33

Gnomad AFR AF: 0.0710

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.0655

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0745

GnomAD4 exome AF: 0.0583 AC: 75592 AN: 1297014 Hom.: 7307 AF XY: 0.0592 AC XY: 38296 AN XY: 646730

African (AFR) AF: 0.0718 AC: 2120 AN: 29542

American (AMR) AF: 0.266 AC: 9674 AN: 36370

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 574 AN: 24590

East Asian (EAS) AF: 0.470 AC: 16960 AN: 36090

South Asian (SAS) AF: 0.117 AC: 9131 AN: 77800

European-Finnish (FIN) AF: 0.0553 AC: 2422 AN: 43774

Middle Eastern (MID) AF: 0.0154 AC: 85 AN: 5512

European-Non Finnish (NFE) AF: 0.0306 AC: 30269 AN: 988330

Other (OTH) AF: 0.0792 AC: 4357 AN: 55006

GnomAD4 genome AF: 0.0789 AC: 12004 AN: 152228 Hom.: 1304 Cov.: 33 AF XY: 0.0851 AC XY: 6337 AN XY: 74428

African (AFR) AF: 0.0711 AC: 2954 AN: 41544

American (AMR) AF: 0.180 AC: 2759 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3470

East Asian (EAS) AF: 0.523 AC: 2705 AN: 5168

South Asian (SAS) AF: 0.134 AC: 643 AN: 4812

European-Finnish (FIN) AF: 0.0655 AC: 695 AN: 10616

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0295 AC: 2005 AN: 68006

Other (OTH) AF: 0.0742 AC: 157 AN: 2116

Alfa AF: 0.0461 Hom.: 144

Bravo AF: 0.0929

Asia WGS AF: 0.297 AC: 1032 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.6
DANN	Benign	0.59
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12312467; hg19: chr12-53184725;