NM_000717.5:c.40C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BS1_SupportingBS2

The NM_000717.5(CA4):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,599,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CA4
NM_000717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: -0.734

Publications

22 publications found

Variant links:

Genes affected

CA4 (HGNC:1375): (carbonic anhydrase 4) 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 a glycosylphosphatidyl-inositol-anchored membrane isozyme expressed on the luminal surfaces of pulmonary (and certain other) capillaries and proximal renal tubules. Its exact function is not known; however, it may have a role in inherited renal abnormalities of bicarbonate transport. [provided by RefSeq, Jul 2008]

CA4 Gene-Disease associations (from GenCC):

retinitis pigmentosa 17
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

CA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 17-60150074-C-T is Pathogenic according to our data. Variant chr17-60150074-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17607.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000138 (21/152366) while in subpopulation NFE AF = 0.000176 (12/68038). AF 95% confidence interval is 0.000102. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA4	NM_000717.5 link	c.40C>T	p.Arg14Trp	missense_variant	Exon 1 of 8	ENST00000300900.9	NP_000708.1	P22748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CA4	ENST00000300900.9 link	c.40C>T	p.Arg14Trp	missense_variant	Exon 1 of 8	1	NM_000717.5	ENSP00000300900.3	P22748-1
CA4	ENST00000585705.5 link	n.133C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3
CA4	ENST00000586876.1 link	n.40C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2		ENSP00000467465.1	P22748-2
CA4	ENST00000591725.1 link	c.-319C>T		5_prime_UTR_variant	Exon 1 of 5	3		ENSP00000466964.1	K7ENI8

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000248

AC:

AN:

221764

AF XY:

0.000242

show subpopulations

Gnomad AFR exome

AF:

0.000151

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000876

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.000536

GnomAD4 exome

AF:

0.000170

AC:

246

AN:

1447000

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

115

AN XY:

720318

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33330

American (AMR)

AF:

0.0000224

AC:

AN:

44602

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.000612

AC:

AN:

40824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5532

European-Non Finnish (NFE)

AF:

0.000177

AC:

197

AN:

1110916

Other (OTH)

AF:

0.000300

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000138

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41596

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

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:

0.000784

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CA4-related disorder

Pathogenic:1

Feb 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CA4 c.40C>T variant is predicted to result in the amino acid substitution p.Arg14Trp. This variant has been reported to be causative for autosomal dominant retinitis pigmentosa in three unrelated families (Rebello et al. 2004. PubMed ID: 15090652; Yang et al. 2005. PubMed ID: 15563508). In one family the variant segregated with disease in 13 affected individuals across three generations (Yang et al. 2005. PubMed ID: 15563508). This variant is reported in 0.081% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Retinitis pigmentosa

Pathogenic:1

May 07, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CA4 c.40C>T (p.Arg14Trp) variant has been reported in at least 37 individuals from three large families with autosomal dominant retinitis pigmentosa. The variant was shown to segregate with disease in at least two of these families (Rebello et al. 2004; Yang et al. 2005). The p.Arg14Trp variant was absent from 36 unaffected family members and 1200 control chromosomes (Rebello et al. 2004; Yang et al. 2005), but is reported at a frequency of 0.00072 in the European (non-Finnish) population of the Exome Aggregation Consortium. Rebello et al. (2004) showed a reduction of CA4 secretion in transfected COS-7 cells carrying the p.Arg14Trp variant, but secretion was comparable to wildtype in a second study that used transfected HEK293 cells (Yang et al. 2005). However, Yang et al. (2005) showed that the p.Arg14Trp variant decreased binding of the CA4 protein to NBC1, thereby disrupting NBC1-mediated recovery of intracellular pH after acid-load. Based on the collective evidence, the p.Arg14Trp variant is classified as pathogenic for autosomal dominant retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinitis pigmentosa 17

Uncertain:1

Jan 15, 2005

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the CA4 protein (p.Arg14Trp). This variant is present in population databases (rs104894559, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 15090652, 15563508). ClinVar contains an entry for this variant (Variation ID: 17607). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CA4 function (PMID: 15090652, 15295099, 15563508, 20626030). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.52

MutationAssessor

Benign

2.0

PhyloP100

-0.73

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.36

Sift

Benign

0.030

Sift4G

Uncertain

0.028

Polyphen

0.99

Vest4

0.22

MVP

0.75

MPC

2.5

ClinPred

0.065

GERP RS

-0.83

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.064

gMVP

0.55

Mutation Taster

=30/70

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over