rs2228063

chr8-85480760-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 0.632

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]

ACMG classification

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	c.754A>G	p.Asn252Asp	missense_variant	7/7	ENST00000285379.10
CA2	NM_001293675.2	c.451A>G	p.Asn151Asp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA2	ENST00000285379.10	c.754A>G	p.Asn252Asp	missense_variant	7/7	1	NM_000067.3	P1
CA2	ENST00000520127.5	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.: 32

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.: 72 AF XY: 0.00485 AC XY: 658 AN XY: 135748

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.: 30 AF XY: 0.00213 AC XY: 1549 AN XY: 727112

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.: 32 AF XY: 0.0253 AC XY: 1882 AN XY: 74480

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.: 44

Bravo AF: 0.0287

ESP6500AA AF: 0.0867 AC: 382

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00832 AC: 1010

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteopetrosis with renal tubular acidosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2020	This variant is associated with the following publications: (PMID: 31690045) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

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	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	9.8
Dann	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.29	N
MutationTaster	Benign	0.0069	A
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.093
Sift	Benign	0.080	T
Sift4G	Benign	0.27	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.82
MPC		0.29
ClinPred		0.0097	T
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

Other links and lift over

dbSNP: rs2228063; hg19: chr8-86392989; COSMIC: COSV99570035; COSMIC: COSV99570035;