chr15-63340371-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001218.5(CA12):​c.664C>T​(p.Arg222Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CA12
NM_001218.5 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0480
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CA12NM_001218.5 linkuse as main transcriptc.664C>T p.Arg222Trp missense_variant 7/11 ENST00000178638.8 NP_001209.1
LOC124903506XR_007064676.1 linkuse as main transcriptn.768-1443G>A 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.664C>T p.Arg222Trp missense_variant 7/111 NM_001218.5 ENSP00000178638 A1O43570-1
CA12ENST00000344366.7 linkuse as main transcriptc.664C>T p.Arg222Trp missense_variant 7/101 ENSP00000343088 P4O43570-2
CA12ENST00000422263.2 linkuse as main transcriptc.484C>T p.Arg162Trp missense_variant 6/92 ENSP00000403028
CA12ENST00000558287.1 linkuse as main transcriptn.212C>T non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152114
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251454
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461834
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152114
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74300
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 12, 2021The c.664C>T (p.R222W) alteration is located in exon 7 (coding exon 7) of the CA12 gene. This alteration results from a C to T substitution at nucleotide position 664, causing the arginine (R) at amino acid position 222 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D;.;.
Eigen
Benign
-0.86
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.11
N
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Benign
0.080
D
MetaRNN
Uncertain
0.49
T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
2.0
M;M;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.22
T
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Benign
0.20
Sift
Uncertain
0.0080
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
0.99
D;D;D
Vest4
0.42
MutPred
0.52
Loss of methylation at R222 (P = 0.0214);Loss of methylation at R222 (P = 0.0214);.;
MVP
0.57
MPC
0.41
ClinPred
0.87
D
GERP RS
-8.8
Varity_R
0.34
gMVP
0.47

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: rs780478289; hg19: chr15-63632570; COSMIC: COSV99457980; API