Genetic Variant NM_007035.4:c.320T>C (chr12-91055962-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_007035.4(KERA):c.320T>C(p.Ile107Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I107R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KERA
NM_007035.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.95

Publications

0 publications found

Variant links:

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

KERA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-91055962-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 225521.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KERA	NM_007035.4	MANE Select	c.320T>C	p.Ile107Thr	missense	Exon 2 of 3	NP_008966.1	O60938

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KERA	ENST00000266719.4	TSL:1 MANE Select	c.320T>C	p.Ile107Thr	missense	Exon 2 of 3	ENSP00000266719.3	O60938

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33328

American (AMR)

AF:

0.00

AC:

AN:

44560

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110730

Other (OTH)

AF:

0.00

AC:

AN:

60262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

4.6

PhyloP100

8.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.89

MutPred

0.68

Gain of catalytic residue at Y110 (P = 0.0101)

MVP

0.96

MPC

0.12

ClinPred

1.0

GERP RS

4.9

Varity_R

0.93

gMVP

0.83

Mutation Taster

=74/26

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over