15-63327234-C-T

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

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 3.76
Variant links:
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
CA12NM_001218.5 linkuse as main transcriptc.908-1G>A splice_acceptor_variant ENST00000178638.8 NP_001209.1
LOC124903506XR_007064676.1 linkuse as main transcriptn.767+8480C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CA12ENST00000178638.8 linkuse as main transcriptc.908-1G>A splice_acceptor_variant 1 NM_001218.5 ENSP00000178638 A1O43570-1
CA12ENST00000344366.7 linkuse as main transcriptc.875-1G>A splice_acceptor_variant 1 ENSP00000343088 P4O43570-2
CA12ENST00000422263.2 linkuse as main transcriptc.695-1G>A splice_acceptor_variant 2 ENSP00000403028
CA12ENST00000560666.1 linkuse as main transcriptn.118-1G>A splice_acceptor_variant, non_coding_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.000434
AC:
66
AN:
152196
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
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:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000852
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000431
AC:
108
AN:
250596
Hom.:
0
AF XY:
0.000377
AC XY:
51
AN XY:
135414
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.0000995
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000925
Gnomad NFE exome
AF:
0.000856
Gnomad OTH exome
AF:
0.000490
GnomAD4 exome
AF:
0.000819
AC:
1197
AN:
1460902
Hom.:
1
Cov.:
30
AF XY:
0.000779
AC XY:
566
AN XY:
726748
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000112
Gnomad4 NFE exome
AF:
0.00102
Gnomad4 OTH exome
AF:
0.000696
GnomAD4 genome
AF:
0.000434
AC:
66
AN:
152196
Hom.:
1
Cov.:
32
AF XY:
0.000336
AC XY:
25
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000852
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000844
Hom.:
0
Bravo
AF:
0.000453
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00156
AC:
6
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00116
AC:
10
ExAC
AF:
0.000436
AC:
53
EpiCase
AF:
0.00104
EpiControl
AF:
0.00137

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 providedliterature onlyOMIMAug 27, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMar 22, 2023- -
Uncertain significance, criteria provided, single submitterresearchBaylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine-- -
Pathogenic, criteria provided, single submitterresearchGarry R Cutting Laboratory, Johns Hopkins UniversityOct 20, 2015- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 01, 2021Canonical 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
27
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Uncertain
0.85
D
MutationTaster
Benign
1.0
D;D;D
GERP RS
5.8

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.30
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.30
Position offset: -1

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.

Other links and lift over

dbSNP: rs148438059; hg19: chr15-63619433; API