rs2071676

chr9-35674056-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.30 (8113 hom., cov: 32)
  • Exomes 𝑓: 0.36 (96268 hom.)
• Consequence: CA9 NM_001216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480

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]

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
CA9	NM_001216.3	c.97G>A	p.Val33Met	missense_variant	1/11	ENST00000378357.9
CA9	XM_047423849.1	c.97G>A	p.Val33Met	missense_variant	1/6
CA9	XM_047423850.1	c.97G>A	p.Val33Met	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA9	ENST00000378357.9	c.97G>A	p.Val33Met	missense_variant	1/11	1	NM_001216.3	P1
ARHGEF39	ENST00000490638.5	c.-341C>T		5_prime_UTR_variant, NMD_transcript_variant	1/12	1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46123 AN: 151984 Hom.: 8108 Cov.: 32

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

GnomAD3 exomes AF: 0.372 AC: 93577 AN: 251290 Hom.: 18509 AF XY: 0.377 AC XY: 51247 AN XY: 135824

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 SAS exome AF: 0.418

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.: 42 AF XY: 0.362 AC XY: 263043 AN XY: 727146

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.366

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.423

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.347

GnomAD4 genome AF: 0.303 AC: 46125 AN: 152102 Hom.: 8113 Cov.: 32 AF XY: 0.309 AC XY: 23006 AN XY: 74344

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.486

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.406

Gnomad4 NFE AF: 0.360

Gnomad4 OTH AF: 0.324

Alfa AF: 0.344 Hom.: 12199

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	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.00080	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	0.97	P
PrimateAI	Benign	0.48	T
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	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.17

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

Other links and lift over

dbSNP: rs2071676; hg19: chr9-35674053; COSMIC: COSV65675780; COSMIC: COSV65675780;