chr12-91056213-C-T

Variant names:

• chr12-91056213-C-T
• rs2735333
• NM_007035.4:c.69G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007035.4(KERA):​c.69G>A​(p.Val23Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 1,609,058 control chromosomes in the GnomAD database, including 471,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (35010 hom., cov: 31)
  • Exomes 𝑓: 0.77 (436914 hom.)
• Consequence: KERA NM_007035.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.08
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-91056213-C-T is Benign according to our data. Variant chr12-91056213-C-T is described in ClinVar as Benign. ClinVar VariationId is 1174695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007035.4. 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
	KERA	NM_007035.4	MANE Select	c.69G>A	p.Val23Val	synonymous	Exon 2 of 3	NP_008966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KERA	ENST00000266719.4	TSL:1 MANE Select	c.69G>A	p.Val23Val	synonymous	Exon 2 of 3	ENSP00000266719.3

Frequencies

GnomAD3 genomes AF: 0.652 AC: 98401 AN: 150820 Hom.: 35004 Cov.: 31

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.749

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.696

GnomAD2 exomes AF: 0.732 AC: 181842 AN: 248542 AF XY: 0.743

Gnomad AFR exome AF: 0.319

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.745

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.828

Gnomad NFE exome AF: 0.782

Gnomad OTH exome AF: 0.761

GnomAD4 exome AF: 0.770 AC: 1123059 AN: 1458120 Hom.: 436914 Cov.: 37 AF XY: 0.771 AC XY: 559110 AN XY: 725406

African (AFR) AF: 0.327 AC: 10884 AN: 33274

American (AMR) AF: 0.661 AC: 29407 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19544 AN: 25990

East Asian (EAS) AF: 0.781 AC: 30944 AN: 39616

South Asian (SAS) AF: 0.741 AC: 63805 AN: 86104

European-Finnish (FIN) AF: 0.824 AC: 43767 AN: 53136

Middle Eastern (MID) AF: 0.741 AC: 4256 AN: 5740

European-Non Finnish (NFE) AF: 0.788 AC: 874814 AN: 1109552

Other (OTH) AF: 0.758 AC: 45638 AN: 60186

GnomAD4 genome AF: 0.652 AC: 98428 AN: 150938 Hom.: 35010 Cov.: 31 AF XY: 0.657 AC XY: 48486 AN XY: 73760

African (AFR) AF: 0.339 AC: 14011 AN: 41316

American (AMR) AF: 0.700 AC: 10559 AN: 15092

Ashkenazi Jewish (ASJ) AF: 0.749 AC: 2581 AN: 3446

East Asian (EAS) AF: 0.797 AC: 4069 AN: 5106

South Asian (SAS) AF: 0.738 AC: 3546 AN: 4806

European-Finnish (FIN) AF: 0.826 AC: 8744 AN: 10592

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.782 AC: 52642 AN: 67284

Other (OTH) AF: 0.694 AC: 1451 AN: 2090

Alfa AF: 0.748 Hom.: 77688

Bravo AF: 0.626

Asia WGS AF: 0.728 AC: 2531 AN: 3478

EpiCase AF: 0.789

EpiControl AF: 0.778

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Cornea plana 2 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.7
DANN	Benign	0.62
PhyloP100		1.1
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: rs2735333; hg19: chr12-91449990; COSMIC: COSV57132160;