dbSNP rs563971993: CA5A:p.Glu241Lys (chr16-87891852-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3PP3PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000530995: 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)" and additional evidence is available in ClinVar.

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:9O:1

Conservation

PhyloP100: 7.21

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen, Ambry Genetics

CA5A links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001739.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000530995: 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); PMID:26913920; SCV001576244: Experimental studies have shown that this missense change affects CA5A function (PMID: 26913920).; SCV003928029: Published functional studies demonstrate a damaging effect with this variant resulting in significantly reduced enzyme stability and activity compared to wildtype. Diez Fernandaz et al., 2006.; SCV005044788: Experimental studies have shown that this missense change affects CA5A function Diez-Fernandez C, et al., 2016.; SCV007097357: "This variant has moderate functional evidence supporting abnormal protein function. Transfected Sf9 cells demonstrated a 75% decrease in enzyme activity and increased thermal instability (PMID: 26913920);"

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, REVEL, 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001739.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA5A	NM_001739.2	MANE Select	c.721G>A	p.Glu241Lys	missense	Exon 6 of 7	NP_001730.1	P35218
CA5A	NM_001367225.1		c.721G>A	p.Glu241Lys	missense	Exon 6 of 7	NP_001354154.1	A0A3B3IRX9
CA5A	NR_159798.1		n.908G>A		non_coding_transcript_exon	Exon 7 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CA5A	ENST00000649794.3	MANE Select	c.721G>A	p.Glu241Lys	missense	Exon 6 of 7	ENSP00000498065.2	P35218
CA5A	ENST00000906212.1		c.856G>A	p.Glu286Lys	missense	Exon 7 of 8	ENSP00000576271.1
CA5A	ENST00000906206.1		c.817G>A	p.Glu273Lys	missense	Exon 7 of 8	ENSP00000576265.1

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

GnomAD2 exomes

AF:

0.000351

AC:

AN:

205068

AF XY:

0.000506

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 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

African (AFR)

AF:

0.00

AC:

AN:

31310

American (AMR)

AF:

0.0000259

AC:

AN:

38628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25252

East Asian (EAS)

AF:

0.00

AC:

AN:

36518

South Asian (SAS)

AF:

0.00271

AC:

220

AN:

81124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5208

European-Non Finnish (NFE)

AF:

0.0000237

AC:

AN:

1097304

Other (OTH)

AF:

0.000221

AC:

AN:

58910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00166

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000453

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency (9)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

4.4

PhyloP100

7.2

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.84

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over