NM_001739.2:c.721G>A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM2PP3PP5_Very_StrongBP4
The NM_001739.2(CA5A):c.721G>A(p.Glu241Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,578,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001739.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000351 AC: 72AN: 205068Hom.: 0 AF XY: 0.000506 AC XY: 57AN XY: 112582
GnomAD4 exome AF: 0.000182 AC: 260AN: 1426546Hom.: 0 Cov.: 30 AF XY: 0.000265 AC XY: 188AN XY: 708674
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74480
ClinVar
Submissions by phenotype
Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency Pathogenic:6Other:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 241 of the CA5A protein (p.Glu241Lys). This variant is present in population databases (rs563971993, gnomAD 0.3%). This missense change has been observed in individuals with carbonic anhydrase VA deficiency (PMID: 26913920, 32381389, 33473334; Invitae). ClinVar contains an entry for this variant (Variation ID: 388645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CA5A protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CA5A function (PMID: 26913920). For these reasons, this variant has been classified as Pathogenic. -
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A Heterozygous Missense variant c.721G>A in Exon 6 of the CA5A gene that results in the amino acid substitution p.Glu241Lys was identified. The observed variant has a maximum allele frequency of 0.00035/0.00003% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic(Variant ID 388645). Published functional studies demonstrate a damaging effect with this variant resulting in significantly reduced enzyme stability and activity compared to wildtype. This variant has been previously reported by Diez Fernandaz et al., 2006. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
The missense variant c.721G>Ap.Glu241Lys in CA5A gene has been reported in homozygous state in individuals with Mitochondrial carbonic anhydrase VA deficiency Konanki R, et al., 2020. Experimental studies have shown that this missense change affects CA5A function Diez-Fernandez C, et al., 2016. The variant is reported with 0.03% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The amino acid Glutamic acid at position 241 is changed to a Lysine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT. The amino acid change p.Glu241Lys in CA5A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Recurrent variant found in majority of affected persons from the Indian subcontinent. -
not provided Pathogenic:1
Published functional studies demonstrate a damaging effect with this variant resulting in significantly reduced enzyme stability and activity compared to wildtype (Diez-Fernandez et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26913920, 34426522, 32381389, 32809955, 32553838, 25834911, 36464834, 36411877, 33473334) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at