Genetic Variant CAT:p.Leu299Val (chr11-34456194-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001752.4(CAT):c.895C>G(p.Leu299Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. L299F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CAT
NM_001752.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.19

Publications

0 publications found

Variant links:

Genes affected

CAT (HGNC:1516): (catalase) This gene encodes catalase, a key antioxidant enzyme in the bodies defense against oxidative stress. Catalase is a heme enzyme that is present in the peroxisome of nearly all aerobic cells. Catalase converts the reactive oxygen species hydrogen peroxide to water and oxygen and thereby mitigates the toxic effects of hydrogen peroxide. Oxidative stress is hypothesized to play a role in the development of many chronic or late-onset diseases such as diabetes, asthma, Alzheimer's disease, systemic lupus erythematosus, rheumatoid arthritis, and cancers. Polymorphisms in this gene have been associated with decreases in catalase activity but, to date, acatalasemia is the only disease known to be caused by this gene. [provided by RefSeq, Oct 2009]

CAT Gene-Disease associations (from GenCC):

acatalasia
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

CAT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24077341).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CAT	NM_001752.4 link	c.895C>G	p.Leu299Val	missense_variant	Exon 7 of 13	ENST00000241052.5	NP_001743.1	P04040A0A384P5Q0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CAT	ENST00000241052.5 link	c.895C>G	p.Leu299Val	missense_variant	Exon 7 of 13	1	NM_001752.4	ENSP00000241052.4	P04040
CAT	ENST00000528104.2 link	n.265C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
CAT	ENST00000650153.1 link	n.*715C>G		non_coding_transcript_exon_variant	Exon 6 of 9			ENSP00000497751.1	A0A3B3ITJ0
CAT	ENST00000650153.1 link	n.*715C>G		3_prime_UTR_variant	Exon 6 of 9			ENSP00000497751.1	A0A3B3ITJ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460490

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726656

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110924

Other (OTH)

AF:

0.00

AC:

AN:

60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

2.4

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.24

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.71

N;N

PhyloP100

-1.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.25

Sift

Benign

0.82

T;.

Sift4G

Benign

0.34

T;.

Polyphen

0.0010

B;B

Vest4

0.33

MutPred

0.73

Gain of methylation at K301 (P = 0.0839);Gain of methylation at K301 (P = 0.0839);

MVP

0.67

MPC

0.12

ClinPred

0.017

GERP RS

-7.6

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.13

gMVP

0.72

Mutation Taster

=93/7

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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11-34456194-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over