rs2228063

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000067.3(CA2):c.754A>G(p.Asn252Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00471 in 1,613,926 control chromosomes in the GnomAD database, including 338 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N252S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.026 ( 185 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 153 hom. )

Consequence

CA2
NM_000067.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:7

Conservation

PhyloP100: 0.632

Publications

13 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 Gene-Disease associations (from GenCC):

autosomal recessive osteopetrosis 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

CA2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000067.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04851392).

BP6

Variant 8-85480760-A-G is Benign according to our data. Variant chr8-85480760-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0879 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA2	NM_000067.3	MANE Select	c.754A>G	p.Asn252Asp	missense	Exon 7 of 7	NP_000058.1	P00918
	CA2	NM_001293675.2		c.451A>G	p.Asn151Asp	missense	Exon 6 of 6	NP_001280604.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA2	ENST00000285379.10	TSL:1 MANE Select	c.754A>G	p.Asn252Asp	missense	Exon 7 of 7	ENSP00000285379.4	P00918
CA2	ENST00000960030.1		c.748A>G	p.Asn250Asp	missense	Exon 7 of 7	ENSP00000630089.1
CA2	ENST00000520127.5	TSL:3	n.*341A>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000428443.1	E5RID5

Frequencies

GnomAD3 genomes

AF:

0.0260

AC:

3957

AN:

152178

Hom.:

184

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0905

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.00680

AC:

1708

AN:

251198

AF XY:

0.00485

show subpopulations

Gnomad AFR exome

AF:

0.0923

Gnomad AMR exome

AF:

0.00493

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00249

AC:

3642

AN:

1461630

Hom.:

153

Cov.:

AF XY:

0.00213

AC XY:

1549

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0896

AC:

2997

AN:

33448

American (AMR)

AF:

0.00551

AC:

246

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000128

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000693

AC:

AN:

1111862

Other (OTH)

AF:

0.00498

AC:

301

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

171

342

512

683

854

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

294

392

490

<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

AF:

0.0260

AC:

3963

AN:

152296

Hom.:

185

Cov.:

AF XY:

0.0253

AC XY:

1882

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0903

AC:

3754

AN:

41552

American (AMR)

AF:

0.0107

AC:

164

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.0147

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

184

369

553

738

922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0107

Hom.:

160

Bravo

AF:

0.0287

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Osteopetrosis with renal tubular acidosis (3)

CARBONIC ANHYDRASE II VARIANT (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.8

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.51

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.29

PhyloP100

0.63

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

REVEL

Benign

0.093

Sift

Benign

0.080

Sift4G

Benign

0.27

Varity_R

0.27

gMVP

0.68

Mutation Taster

=94/6

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over