rs104894559
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
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
NM_000717.5 missense
Scores
1
6
12
Clinical Significance
Conservation
PhyloP100: -0.734
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 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 id is 17607.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr17-60150074-C-T is described in Lovd as [Pathogenic].
BS2
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CA4 | NM_000717.5 | c.40C>T | p.Arg14Trp | missense_variant | 1/8 | ENST00000300900.9 | NP_000708.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CA4 | ENST00000300900.9 | c.40C>T | p.Arg14Trp | missense_variant | 1/8 | 1 | NM_000717.5 | ENSP00000300900.3 | ||
CA4 | ENST00000591725.1 | c.-319C>T | 5_prime_UTR_variant | 1/5 | 3 | ENSP00000466964.1 | ||||
CA4 | ENST00000585705.5 | n.133C>T | non_coding_transcript_exon_variant | 1/3 | 3 | |||||
CA4 | ENST00000586876.1 | n.40C>T | non_coding_transcript_exon_variant | 1/6 | 2 | ENSP00000467465.1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152248Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000248 AC: 55AN: 221764Hom.: 0 AF XY: 0.000242 AC XY: 30AN XY: 123816
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GnomAD4 exome AF: 0.000170 AC: 246AN: 1447000Hom.: 0 Cov.: 31 AF XY: 0.000160 AC XY: 115AN XY: 720318
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152366Hom.: 0 Cov.: 31 AF XY: 0.000134 AC XY: 10AN XY: 74506
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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
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | 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
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 07, 2018 | 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
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 15, 2005 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Benign
M
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Benign
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at