15-63340370-C-T

Position:

chr15-63340370-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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 (★). 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

Clinical Significance

Benign criteria provided, single submitter 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]

CA12 links:

LOC124903506 (HGNC:):

LOC124903506 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 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 criteria_provided_single_submitter, 1 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
CA12	NM_001218.5 linkuse as main transcript	c.665G>A	p.Arg222Gln	missense_variant	7/11	ENST00000178638.8
LOC124903506	XR_007064676.1 linkuse as main transcript	n.768-1444C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA12	ENST00000178638.8 linkuse as main transcript	c.665G>A	p.Arg222Gln	missense_variant	7/11	1	NM_001218.5	A1	O43570-1
CA12	ENST00000344366.7 linkuse as main transcript	c.665G>A	p.Arg222Gln	missense_variant	7/10	1		P4	O43570-2
CA12	ENST00000422263.2 linkuse as main transcript	c.485G>A	p.Arg162Gln	missense_variant	6/9	2
CA12	ENST00000558287.1 linkuse as main transcript	n.213G>A		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000881

AC:

134

AN:

152126

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.00128

AC XY:

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.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00388

AC:

471

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CA12-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This 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

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

LIST_S2

Benign

0.44

T;T;T

MetaRNN

Benign

0.0091

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.25

N;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.21

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over