rs148438059

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001218.5(CA12):c.908-1G>A variant causes a splice acceptor, intron 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, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 3.76

Publications

8 publications found

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]

CA12 Gene-Disease associations (from GenCC):

isolated hyperchlorhidrosis
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

CA12 links:

LOC124903506 (HGNC:):

LOC124903506 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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 VariationId is 218369.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001218.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CA12	NM_001218.5	MANE Select	c.908-1G>A	splice_acceptor intron	N/A	NP_001209.1	O43570-1
CA12	NM_206925.3		c.875-1G>A	splice_acceptor intron	N/A	NP_996808.1	O43570-2
CA12	NM_001293642.2		c.695-1G>A	splice_acceptor intron	N/A	NP_001280571.1	B3KUB4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CA12	ENST00000178638.8	TSL:1 MANE Select	c.908-1G>A	splice_acceptor intron	N/A	ENSP00000178638.3	O43570-1
CA12	ENST00000344366.7	TSL:1	c.875-1G>A	splice_acceptor intron	N/A	ENSP00000343088.3	O43570-2
CA12	ENST00000907869.1		c.902-1G>A	splice_acceptor intron	N/A	ENSP00000577928.1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152196

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000431

AC:

108

AN:

250596

AF XY:

0.000377

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 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.:

Cov.:

AF XY:

0.000779

AC XY:

566

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33462

American (AMR)

AF:

0.0000895

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00102

AC:

1139

AN:

1111370

Other (OTH)

AF:

0.000696

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<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:

0.000434

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000852

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000768

Hom.:

Bravo

AF:

0.000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00137

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Isolated hyperchlorhidrosis (5)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Uncertain

0.85

PhyloP100

3.8

GERP RS

5.8

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over