12-91051526-G-A

Position:

• chr12-91051526-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000266719.4(KERA):​c.887-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,589,822 control chromosomes in the GnomAD database, including 46,607 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3137 hom., cov: 32)
  • Exomes 𝑓: 0.24 (43470 hom.)
• Consequence: KERA ENST00000266719.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001873
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.235

Genes affected

KERA (HGNC:6309): (keratocan) The protein encoded by this gene is a keratan sulfate proteoglycan that is involved in corneal transparency. Defects in this gene are a cause of autosomal recessive cornea plana 2 (CNA2).[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-91051526-G-A is Benign according to our data. Variant chr12-91051526-G-A is described in ClinVar as [Benign]. Clinvar id is 1530150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-91051526-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KERA	NM_007035.4	c.887-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000266719.4	NP_008966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KERA	ENST00000266719.4	c.887-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007035.4	ENSP00000266719	P1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27644 AN: 151432 Hom.: 3137 Cov.: 32

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.183

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.194 AC: 48409 AN: 249190 Hom.: 5585 AF XY: 0.197 AC XY: 26556 AN XY: 134664

Gnomad AFR exome AF: 0.0592

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.00994

Gnomad SAS exome AF: 0.146

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.250

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.236 AC: 339190 AN: 1438272 Hom.: 43470 Cov.: 27 AF XY: 0.234 AC XY: 167852 AN XY: 716714

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.00536

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.216

GnomAD4 genome AF: 0.182 AC: 27639 AN: 151550 Hom.: 3137 Cov.: 32 AF XY: 0.180 AC XY: 13318 AN XY: 74028

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.208

Gnomad4 EAS AF: 0.0115

Gnomad4 SAS AF: 0.135

Gnomad4 FIN AF: 0.289

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.179

Alfa AF: 0.233 Hom.: 4820

Bravo AF: 0.168

Asia WGS AF: 0.0720 AC: 250 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0020
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: rs2701166; hg19: chr12-91445303; COSMIC: COSV57130712;