rs2701166

Variant names:

• chr12-91051526-G-A
• rs2701166
• NM_007035.4:c.887-8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007035.4(KERA):​c.887-8C>T variant causes a splice region, 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 NM_007035.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001873
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.235
• Publications: 11 publications found

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]

KERA Gene-Disease associations (from GenCC):

• cornea plana

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• cornea plana 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• congenital cornea plana

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1530150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
KERA	NM_007035.4	c.887-8C>T		splice_region_variant, intron_variant	Intron 2 of 2	ENST00000266719.4	NP_008966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KERA	ENST00000266719.4	c.887-8C>T		splice_region_variant, intron_variant	Intron 2 of 2	1	NM_007035.4	ENSP00000266719.3

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

GnomAD2 exomes AF: 0.194 AC: 48409 AN: 249190 AF XY: 0.197

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 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

African (AFR) AF: 0.0567 AC: 1873 AN: 33042

American (AMR) AF: 0.154 AC: 6829 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 5450 AN: 25892

East Asian (EAS) AF: 0.00536 AC: 212 AN: 39568

South Asian (SAS) AF: 0.148 AC: 12721 AN: 85860

European-Finnish (FIN) AF: 0.284 AC: 15097 AN: 53084

Middle Eastern (MID) AF: 0.179 AC: 1020 AN: 5704

European-Non Finnish (NFE) AF: 0.260 AC: 283159 AN: 1091124

Other (OTH) AF: 0.216 AC: 12829 AN: 59522

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

African (AFR) AF: 0.0670 AC: 2777 AN: 41454

American (AMR) AF: 0.172 AC: 2603 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 719 AN: 3456

East Asian (EAS) AF: 0.0115 AC: 59 AN: 5128

South Asian (SAS) AF: 0.135 AC: 651 AN: 4818

European-Finnish (FIN) AF: 0.289 AC: 3051 AN: 10558

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17174 AN: 67658

Other (OTH) AF: 0.179 AC: 376 AN: 2106

Alfa AF: 0.229 Hom.: 10682

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.21
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2701166; hg19: chr12-91445303; COSMIC: COSV57130712;