rs2071676

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001216.3(CA9):c.97G>A(p.Val33Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,613,758 control chromosomes in the GnomAD database, including 104,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8113 hom., cov: 32)

Exomes 𝑓: 0.36 ( 96268 hom. )

Consequence

CA9
NM_001216.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.480

Publications

46 publications found

Variant links:

Genes affected

CA9 (HGNC:1383): (carbonic anhydrase 9) 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. They show extensive diversity in tissue distribution and in their subcellular localization. CA IX is a transmembrane protein and is one of only two tumor-associated carbonic anhydrase isoenzymes known. It is expressed in all clear-cell renal cell carcinoma, but is not detected in normal kidney or most other normal tissues. It may be involved in cell proliferation and transformation. This gene was mapped to 17q21.2 by fluorescence in situ hybridization, however, radiation hybrid mapping localized it to 9p13-p12. [provided by RefSeq, Jun 2014]

CA9 links:

ARHGEF39 (HGNC:25909): (Rho guanine nucleotide exchange factor 39) Predicted to enable guanyl-nucleotide exchange factor activity. Involved in positive regulation of cell migration. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ARHGEF39 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.030832E-4).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA9	NM_001216.3 link	c.97G>A	p.Val33Met	missense_variant	Exon 1 of 11	ENST00000378357.9	NP_001207.2	Q16790A0A0S2Z3D0
CA9	XM_047423849.1 link	c.97G>A	p.Val33Met	missense_variant	Exon 1 of 6		XP_047279805.1
CA9	XM_047423850.1 link	c.97G>A	p.Val33Met	missense_variant	Exon 1 of 6		XP_047279806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CA9	ENST00000378357.9 link	c.97G>A	p.Val33Met	missense_variant	Exon 1 of 11	1	NM_001216.3	ENSP00000367608.4	Q16790
ARHGEF39	ENST00000490638.5 link	n.-341C>T		non_coding_transcript_exon_variant	Exon 1 of 12	1		ENSP00000436756.1	Q8N4T4-2
ARHGEF39	ENST00000490638.5 link	n.-341C>T		5_prime_UTR_variant	Exon 1 of 12	1		ENSP00000436756.1	Q8N4T4-2

Frequencies

GnomAD3 genomes

AF:

0.303

AC:

46123

AN:

151984

Hom.:

8108

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.448

Gnomad AMR

AF:

0.374

Gnomad ASJ

AF:

0.352

Gnomad EAS

AF:

0.485

Gnomad SAS

AF:

0.430

Gnomad FIN

AF:

0.406

Gnomad MID

AF:

0.418

Gnomad NFE

AF:

0.360

Gnomad OTH

AF:

0.326

GnomAD2 exomes

AF:

0.372

AC:

93577

AN:

251290

AF XY:

0.377

show subpopulations

Gnomad AFR exome

AF:

0.101

Gnomad AMR exome

AF:

0.435

Gnomad ASJ exome

AF:

0.373

Gnomad EAS exome

AF:

0.501

Gnomad FIN exome

AF:

0.405

Gnomad NFE exome

AF:

0.354

Gnomad OTH exome

AF:

0.349

GnomAD4 exome

AF:

0.359

AC:

524460

AN:

1461656

Hom.:

96268

Cov.:

AF XY:

0.362

AC XY:

263043

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.103

AC:

3462

AN:

33480

American (AMR)

AF:

0.430

AC:

19240

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

9568

AN:

26134

East Asian (EAS)

AF:

0.475

AC:

18865

AN:

39694

South Asian (SAS)

AF:

0.423

AC:

36448

AN:

86254

European-Finnish (FIN)

AF:

0.403

AC:

21499

AN:

53408

Middle Eastern (MID)

AF:

0.389

AC:

2241

AN:

5768

European-Non Finnish (NFE)

AF:

0.353

AC:

392164

AN:

1111812

Other (OTH)

AF:

0.347

AC:

20973

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

18741

37481

56222

74962

93703

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12548

25096

37644

50192

62740

<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:

0.303

AC:

46125

AN:

152102

Hom.:

8113

Cov.:

AF XY:

0.309

AC XY:

23006

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.111

AC:

4605

AN:

41538

American (AMR)

AF:

0.374

AC:

5717

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.352

AC:

1222

AN:

3472

East Asian (EAS)

AF:

0.486

AC:

2499

AN:

5144

South Asian (SAS)

AF:

0.431

AC:

2076

AN:

4816

European-Finnish (FIN)

AF:

0.406

AC:

4300

AN:

10580

Middle Eastern (MID)

AF:

0.408

AC:

120

AN:

294

European-Non Finnish (NFE)

AF:

0.360

AC:

24492

AN:

67952

Other (OTH)

AF:

0.324

AC:

686

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1541

3083

4624

6166

7707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<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:

0.339

Hom.:

16065

Bravo

AF:

0.292

ESP6500AA

AF:

0.115

AC:

507

ESP6500EA

AF:

0.348

AC:

2993

ExAC

AF:

0.362

AC:

43914

Asia WGS

AF:

0.375

AC:

1306

AN:

3478

EpiCase

AF:

0.352

EpiControl

AF:

0.349

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.56

T;T

MetaRNN

Benign

0.00080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.

PhyloP100

0.48

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.49

N;.

REVEL

Benign

0.18

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.72

P;.

Vest4

0.22

MPC

0.15

ClinPred

0.020

GERP RS

3.1

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over