rs3829078

Positions:

• chr9-35679254-A-G
• chr9-35679254-A-T

Variant summary

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

The NM_001216.3(CA9):​c.977A>G​(p.Gln326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0999 in 1,614,030 control chromosomes in the GnomAD database, including 9,096 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.075 (507 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8589 hom.)
• Consequence: CA9 NM_001216.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033312142).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA9	NM_001216.3	c.977A>G	p.Gln326Arg	missense_variant	7/11	ENST00000378357.9
CA9	XM_047423849.1	c.910A>G	p.Asn304Asp	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA9	ENST00000378357.9	c.977A>G	p.Gln326Arg	missense_variant	7/11	1	NM_001216.3	P1
CA9	ENST00000493245.1	n.181A>G		non_coding_transcript_exon_variant	3/7	5

Frequencies

GnomAD3 genomes AF: 0.0750 AC: 11408 AN: 152110 Hom.: 506 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0804

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0822

GnomAD3 exomes AF: 0.0817 AC: 20544 AN: 251462 Hom.: 1043 AF XY: 0.0817 AC XY: 11106 AN XY: 135912

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0756

Gnomad ASJ exome AF: 0.0497

Gnomad EAS exome AF: 0.0346

Gnomad SAS exome AF: 0.0585

Gnomad FIN exome AF: 0.0616

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.0784

GnomAD4 exome AF: 0.102 AC: 149835 AN: 1461802 Hom.: 8589 Cov.: 32 AF XY: 0.102 AC XY: 73834 AN XY: 727214

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.0746

Gnomad4 ASJ exome AF: 0.0493

Gnomad4 EAS exome AF: 0.0244

Gnomad4 SAS exome AF: 0.0607

Gnomad4 FIN exome AF: 0.0614

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.0919

GnomAD4 genome AF: 0.0750 AC: 11418 AN: 152228 Hom.: 507 Cov.: 32 AF XY: 0.0720 AC XY: 5357 AN XY: 74410

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.0805

Gnomad4 ASJ AF: 0.0444

Gnomad4 EAS AF: 0.0307

Gnomad4 SAS AF: 0.0541

Gnomad4 FIN AF: 0.0634

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0842

Alfa AF: 0.101 Hom.: 2179

Bravo AF: 0.0757

TwinsUK AF: 0.121 AC: 448

ALSPAC AF: 0.111 AC: 429

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.113 AC: 969

ExAC AF: 0.0820 AC: 9962

Asia WGS AF: 0.0620 AC: 215 AN: 3478

EpiCase AF: 0.110

EpiControl AF: 0.106

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.66
DEOGEN2	Benign	0.064	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.0	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	2.0	N;.
REVEL	Benign	0.043
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;.
Vest4		0.052
MPC		0.16
ClinPred		0.00019	T
GERP RS		2.5
Varity_R		0.27
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3829078; hg19: chr9-35679251; COSMIC: COSV61405203; COSMIC: COSV61405203;