9-35676147-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001216.3(CA9):c.688G>A(p.Gly230Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,613,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
CA9
NM_001216.3 missense
NM_001216.3 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 6.68
Genes affected
CA9 (HGNC:1383): (carbonic anhydrase 9) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. CA IX is a transmembrane protein and is one of only two tumor-associated carbonic anhydrase isoenzymes known. It is expressed in all clear-cell renal cell carcinoma, but is not detected in normal kidney or most other normal tissues. It may be involved in cell proliferation and transformation. This gene was mapped to 17q21.2 by fluorescence in situ hybridization, however, radiation hybrid mapping localized it to 9p13-p12. [provided by RefSeq, Jun 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CA9 | NM_001216.3 | c.688G>A | p.Gly230Arg | missense_variant | 4/11 | ENST00000378357.9 | |
CA9 | XM_047423849.1 | c.688G>A | p.Gly230Arg | missense_variant | 4/6 | ||
CA9 | XM_047423850.1 | c.688G>A | p.Gly230Arg | missense_variant | 4/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CA9 | ENST00000378357.9 | c.688G>A | p.Gly230Arg | missense_variant | 4/11 | 1 | NM_001216.3 | P1 | |
CA9 | ENST00000493245.1 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152252Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000242 AC: 6AN: 247826Hom.: 0 AF XY: 0.0000223 AC XY: 3AN XY: 134342
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GnomAD4 exome AF: 0.0000294 AC: 43AN: 1460944Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 28AN XY: 726792
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74376
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 06, 2022 | The c.688G>A (p.G230R) alteration is located in exon 4 (coding exon 4) of the CA9 gene. This alteration results from a G to A substitution at nucleotide position 688, causing the glycine (G) at amino acid position 230 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at