8-85465289-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_000067.3(CA2):c.52A>G(p.Lys18Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,734 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K18Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CA2
NM_000067.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.252

Publications

8 publications found

Variant links:

Genes affected

CA2 (HGNC:1373): (carbonic anhydrase 2) The protein encoded by this gene is one of several isozymes of carbonic anhydrase, which catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

CA2 links:

CA3-AS1 (HGNC:51657): (CA3 antisense RNA 1)

CA3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-85465289-A-G is Pathogenic according to our data. Variant chr8-85465289-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 914.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.28768873). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000067.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CA2	NM_000067.3	MANE Select	c.52A>G	p.Lys18Glu	missense	Exon 2 of 7	NP_000058.1
CA2	NM_001293675.2		c.-133A>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 6	NP_001280604.1
CA2	NM_001293675.2		c.-133A>G		5_prime_UTR	Exon 2 of 6	NP_001280604.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CA2	ENST00000285379.10	TSL:1 MANE Select	c.52A>G	p.Lys18Glu	missense	Exon 2 of 7	ENSP00000285379.4
CA2	ENST00000518231.1	TSL:2	n.123A>G		non_coding_transcript_exon	Exon 2 of 3
CA2	ENST00000520127.5	TSL:3	n.52A>G		non_coding_transcript_exon	Exon 2 of 6	ENSP00000428443.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251464

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60392

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CARBONIC ANHYDRASE II VARIANT

Pathogenic:1

Oct 01, 1982

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.12

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.80

M_CAP

Benign

0.044

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.85

MutationAssessor

Benign

-0.27

PhyloP100

0.25

PrimateAI

Benign

0.30

PROVEAN

Benign

0.090

REVEL

Benign

0.11

Sift

Benign

0.81

Sift4G

Benign

0.87

Polyphen

0.0

Vest4

0.15

MutPred

0.44

Loss of ubiquitination at K18 (P = 0.0081)

MVP

0.63

MPC

0.36

ClinPred

0.031

GERP RS

1.6

Varity_R

0.58

gMVP

0.59

Mutation Taster

=37/63

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over