chrX-15775292-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_007220.4(CA5B):c.602C>T(p.Pro201Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,196,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000041 ( 0 hom. 18 hem. )

Consequence

CA5B
NM_007220.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.46

Variant links:

Genes affected

CA5B (HGNC:1378): (carbonic anhydrase 5B) 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. This gene encodes carbonic anhydrase 5B. CA5B, and the related CA5A gene, has its expression localized in the mitochondria though CA5B has a wider tissue distribution than CA5A, which is restricted to the liver, kidneys, and skeletal muscle. A carbonic anhydrase pseudogene (CA5BP1) is adjacent to the CA5B gene and these two loci produce CA5BP1-CA5B readthrough transcripts. [provided by RefSeq, Jan 2019]

CA5B links:

CA5BP1-CA5B (HGNC:):

CA5BP1-CA5B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

BS2

High Hemizygotes in GnomAdExome4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA5B	NM_007220.4 link	c.602C>T	p.Pro201Leu	missense_variant	Exon 6 of 8	ENST00000318636.8	NP_009151.1	Q9Y2D0A0A024RBW9
CA5BP1-CA5B	NR_160544.1 link	n.2017C>T		non_coding_transcript_exon_variant	Exon 10 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA5B	ENST00000318636.8 link	c.602C>T	p.Pro201Leu	missense_variant	Exon 6 of 8	1	NM_007220.4	ENSP00000314099.3		Q9Y2D0
CA5B	ENST00000496188.1 link	n.176C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112463

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34629

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000750

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000114

AC:

AN:

175745

Hom.:

AF XY:

0.0000164

AC XY:

AN XY:

60873

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000393

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000406

AC:

AN:

1084521

Hom.:

Cov.:

AF XY:

0.0000512

AC XY:

AN XY:

351239

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000875

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000334

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.0000220

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112463

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34629

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000750

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.602C>T (p.P201L) alteration is located in exon 6 (coding exon 5) of the CA5B gene. This alteration results from a C to T substitution at nucleotide position 602, causing the proline (P) at amino acid position 201 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.17

.;T

M_CAP

Uncertain

0.090

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

0.025

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Uncertain

0.37

Sift

Benign

0.033

D;D

Sift4G

Benign

0.26

T;T

Polyphen

1.0

D;D

Vest4

0.68

MutPred

0.41

Loss of ubiquitination at K206 (P = 0.073);Loss of ubiquitination at K206 (P = 0.073);

MVP

0.95

MPC

0.54

ClinPred

0.92

GERP RS

5.4

Varity_R

0.59

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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