15-63327234-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001218.5(CA12):c.908-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000783 in 1,613,098 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00043 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00082 ( 1 hom. )
Consequence
CA12
NM_001218.5 splice_acceptor
NM_001218.5 splice_acceptor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.76
Genes affected
CA12 (HGNC:1371): (carbonic anhydrase 12) 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. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Three transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2014]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PP5
Variant 15-63327234-C-T is Pathogenic according to our data. Variant chr15-63327234-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218369.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CA12 | NM_001218.5 | c.908-1G>A | splice_acceptor_variant | ENST00000178638.8 | NP_001209.1 | |||
LOC124903506 | XR_007064676.1 | n.767+8480C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CA12 | ENST00000178638.8 | c.908-1G>A | splice_acceptor_variant | 1 | NM_001218.5 | ENSP00000178638 | A1 | |||
CA12 | ENST00000344366.7 | c.875-1G>A | splice_acceptor_variant | 1 | ENSP00000343088 | P4 | ||||
CA12 | ENST00000422263.2 | c.695-1G>A | splice_acceptor_variant | 2 | ENSP00000403028 | |||||
CA12 | ENST00000560666.1 | n.118-1G>A | splice_acceptor_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000434 AC: 66AN: 152196Hom.: 1 Cov.: 32
GnomAD3 genomes
AF:
AC:
66
AN:
152196
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000431 AC: 108AN: 250596Hom.: 0 AF XY: 0.000377 AC XY: 51AN XY: 135414
GnomAD3 exomes
AF:
AC:
108
AN:
250596
Hom.:
AF XY:
AC XY:
51
AN XY:
135414
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000819 AC: 1197AN: 1460902Hom.: 1 Cov.: 30 AF XY: 0.000779 AC XY: 566AN XY: 726748
GnomAD4 exome
AF:
AC:
1197
AN:
1460902
Hom.:
Cov.:
30
AF XY:
AC XY:
566
AN XY:
726748
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000434 AC: 66AN: 152196Hom.: 1 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74342
GnomAD4 genome
AF:
AC:
66
AN:
152196
Hom.:
Cov.:
32
AF XY:
AC XY:
25
AN XY:
74342
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
1
ALSPAC
AF:
AC:
6
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
10
ExAC
AF:
AC:
53
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Isolated hyperchlorhidrosis Pathogenic:3Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 27, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | research | Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine | - | - - |
Pathogenic, criteria provided, single submitter | research | Garry R Cutting Laboratory, Johns Hopkins University | Oct 20, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2021 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that this variant leads to undetectable protein expression compared to wild type protein (Lee et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 26911677) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at