15-63340370-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001218.5(CA12):​c.665G>A​(p.Arg222Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,118 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R222W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00088 ( 4 hom., cov: 32)
Exomes 𝑓: 0.0016 ( 56 hom. )

Consequence

CA12
NM_001218.5 missense

Scores

18

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.870
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 Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.009084135).
BP6
Variant 15-63340370-C-T is Benign according to our data. Variant chr15-63340370-C-T is described in ClinVar as [Benign]. Clinvar id is 3038552.Status of the report is no_assertion_criteria_provided, 0 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00088 (134/152244) while in subpopulation SAS AF= 0.0266 (128/4810). AF 95% confidence interval is 0.0229. There are 4 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CA12NM_001218.5 linkuse as main transcriptc.665G>A p.Arg222Gln missense_variant 7/11 ENST00000178638.8
LOC124903506XR_007064676.1 linkuse as main transcriptn.768-1444C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CA12ENST00000178638.8 linkuse as main transcriptc.665G>A p.Arg222Gln missense_variant 7/111 NM_001218.5 A1O43570-1
CA12ENST00000344366.7 linkuse as main transcriptc.665G>A p.Arg222Gln missense_variant 7/101 P4O43570-2
CA12ENST00000422263.2 linkuse as main transcriptc.485G>A p.Arg162Gln missense_variant 6/92
CA12ENST00000558287.1 linkuse as main transcriptn.213G>A non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.000881
AC:
134
AN:
152126
Hom.:
4
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0266
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00326
AC:
820
AN:
251456
Hom.:
22
AF XY:
0.00442
AC XY:
600
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0258
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.00161
AC:
2355
AN:
1461874
Hom.:
56
Cov.:
31
AF XY:
0.00226
AC XY:
1644
AN XY:
727236
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0252
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000710
Gnomad4 OTH exome
AF:
0.00159
GnomAD4 genome
AF:
0.000880
AC:
134
AN:
152244
Hom.:
4
Cov.:
32
AF XY:
0.00128
AC XY:
95
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.0266
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.000144
Hom.:
0
Bravo
AF:
0.000159
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00388
AC:
471
Asia WGS
AF:
0.00924
AC:
32
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

CA12-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 22, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
6.5
DANN
Benign
0.86
DEOGEN2
Benign
0.054
T;.;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0056
N
LIST_S2
Benign
0.44
T;T;T
MetaRNN
Benign
0.0091
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
-0.25
N;N;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
0.54
N;N;N
REVEL
Benign
0.13
Sift
Benign
0.26
T;T;T
Sift4G
Benign
0.54
T;T;T
Polyphen
0.0030
B;B;B
Vest4
0.21
MVP
0.30
MPC
0.18
ClinPred
0.010
T
GERP RS
-7.0
Varity_R
0.13
gMVP
0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs151338276; hg19: chr15-63632569; COSMIC: COSV51605997; API