rs563971993

Positions:

chr16-87891852-C-T

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

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CA5A
NM_001739.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 7.21

Variant links:

Genes affected

CA5A (HGNC:1377): (carbonic anhydrase 5A) 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 VA is localized in the mitochondria and expressed primarily in the liver. It may play an important role in ureagenesis and gluconeogenesis. CA5A gene maps to chromosome 16q24.3 and an unprocessed pseudogene has been assigned to 16p12-p11.2. [provided by RefSeq, Jul 2008]

CA5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 16-87891852-C-T is Pathogenic according to our data. Variant chr16-87891852-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 388645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.21234831). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA5A	NM_001739.2 linkuse as main transcript	c.721G>A	p.Glu241Lys	missense_variant	6/7	ENST00000649794.3	NP_001730.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA5A	ENST00000649794.3 linkuse as main transcript	c.721G>A	p.Glu241Lys	missense_variant	6/7		NM_001739.2	ENSP00000498065	P1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000351

AC:

AN:

205068

Hom.:

AF XY:

0.000506

AC XY:

AN XY:

112582

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00271

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000425

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000182

AC:

260

AN:

1426546

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

188

AN XY:

708674

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000259

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00271

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000237

Gnomad4 OTH exome

AF:

0.000221

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.000430

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Pathogenic:6Other:1

not provided, no classification provided	literature only	GeneReviews	-	Recurrent variant found in majority of affected persons from the Indian subcontinent. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 06, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2022	This variant is present in population databases (rs563971993, gnomAD 0.3%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CA5A function (PMID: 26913920). 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. ClinVar contains an entry for this variant (Variation ID: 388645). This missense change has been observed in individuals with carbonic anhydrase VA deficiency (PMID: 26913920, 32381389, 33473334; Invitae). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2023

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

T;.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.4

H;.;H

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.9

D;.;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0020

D;.;.

Polyphen

1.0

D;.;D

Vest4

0.98

MVP

0.89

MPC

0.31

ClinPred

0.89

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.84

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