rs12553173

chr9-35674104-T-Cchr9-35674104-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001216.3(CA9):c.145T>C(p.Leu49=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,850 control chromosomes in the GnomAD database, including 19,483 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (4006 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15477 hom.)
• Consequence: CA9 NM_001216.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.26

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA9	NM_001216.3	c.145T>C	p.Leu49=	synonymous_variant	1/11	ENST00000378357.9
CA9	XM_047423849.1	c.145T>C	p.Leu49=	synonymous_variant	1/6
CA9	XM_047423850.1	c.145T>C	p.Leu49=	synonymous_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA9	ENST00000378357.9	c.145T>C	p.Leu49=	synonymous_variant	1/11	1	NM_001216.3	P1
ARHGEF39	ENST00000490638.5	c.-389A>G		5_prime_UTR_variant, NMD_transcript_variant	1/12	1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30238 AN: 151904 Hom.: 3987 Cov.: 32

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.140 AC: 35150 AN: 251306 Hom.: 3229 AF XY: 0.133 AC XY: 18038 AN XY: 135844

Gnomad AFR exome AF: 0.390

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0653

Gnomad EAS exome AF: 0.169

Gnomad SAS exome AF: 0.0919

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.138 AC: 201253 AN: 1461828 Hom.: 15477 Cov.: 35 AF XY: 0.136 AC XY: 98650 AN XY: 727222

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.0647

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.0956

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.199 AC: 30319 AN: 152022 Hom.: 4006 Cov.: 32 AF XY: 0.195 AC XY: 14477 AN XY: 74300

Gnomad4 AFR AF: 0.382

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.0654

Gnomad4 EAS AF: 0.167

Gnomad4 SAS AF: 0.0990

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.174

Alfa AF: 0.158 Hom.: 1612

Bravo AF: 0.211

Asia WGS AF: 0.150 AC: 521 AN: 3478

EpiCase AF: 0.129

EpiControl AF: 0.128

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.062
Dann	Benign	0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12553173; hg19: chr9-35674101; COSMIC: COSV65675172; COSMIC: COSV65675172;