rs2228063

Positions:

chr8-85480760-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_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. 14/20 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:6

Conservation

PhyloP100: 0.632

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a domain Alpha-carbonic anhydrase (size 256) in uniprot entity CAH2_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_000067.3

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 [Likely_benign]. Clinvar id is 913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-85480760-A-G is described in Lovd as [Likely_benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA2	NM_000067.3 linkuse as main transcript	c.754A>G	p.Asn252Asp	missense_variant	7/7	ENST00000285379.10
CA2	NM_001293675.2 linkuse as main transcript	c.451A>G	p.Asn151Asp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA2	ENST00000285379.10 linkuse as main transcript	c.754A>G	p.Asn252Asp	missense_variant	7/7	1	NM_000067.3	P1
CA2	ENST00000520127.5 linkuse as main transcript	c.*341A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	3

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

GnomAD3 exomes

AF:

0.00680

AC:

1708

AN:

251198

Hom.:

AF XY:

0.00485

AC XY:

658

AN XY:

135748

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 SAS exome

AF:

0.000131

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

Gnomad4 AFR exome

AF:

0.0896

Gnomad4 AMR exome

AF:

0.00551

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.00498

GnomAD4 genome

AF:

0.0260

AC:

3963

AN:

152296

Hom.:

185

Cov.:

AF XY:

0.0253

AC XY:

1882

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0903

Gnomad4 AMR

AF:

0.0107

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.00484

Hom.:

Bravo

AF:

0.0287

ESP6500AA

AF:

0.0867

AC:

382

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00832

AC:

1010

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2020	This variant is associated with the following publications: (PMID: 31690045) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Osteopetrosis with renal tubular acidosis

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

CARBONIC ANHYDRASE II VARIANT

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 25, 1972

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.8

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

MutationTaster

Benign

0.0069

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.4

REVEL

Benign

0.093

Sift

Benign

0.080

Sift4G

Benign

0.27

Polyphen

0.0

Vest4

0.10

MVP

0.82

MPC

0.29

ClinPred

0.0097

GERP RS

0.28

Varity_R

0.27

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over