NM_001216.3:c.145T>C

Variant names:

• chr9-35674104-T-C
• rs12553173
• NM_001216.3:c.145T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001216.3(CA9):​c.145T>C​(p.Leu49Leu) 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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	NM_001216.3	MANE Select	c.145T>C	p.Leu49Leu	synonymous	Exon 1 of 11	NP_001207.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	ENST00000378357.9	TSL:1 MANE Select	c.145T>C	p.Leu49Leu	synonymous	Exon 1 of 11	ENSP00000367608.4
	ARHGEF39	ENST00000490638.5	TSL:1	n.-389A>G		non_coding_transcript_exon	Exon 1 of 12	ENSP00000436756.1
	ARHGEF39	ENST00000490638.5	TSL:1	n.-389A>G		5_prime_UTR	Exon 1 of 12	ENSP00000436756.1

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

GnomAD2 exomes AF: 0.140 AC: 35150 AN: 251306 AF XY: 0.133

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 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

African (AFR) AF: 0.388 AC: 12981 AN: 33480

American (AMR) AF: 0.103 AC: 4594 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0647 AC: 1690 AN: 26134

East Asian (EAS) AF: 0.150 AC: 5967 AN: 39698

South Asian (SAS) AF: 0.0956 AC: 8242 AN: 86256

European-Finnish (FIN) AF: 0.127 AC: 6791 AN: 53418

Middle Eastern (MID) AF: 0.0963 AC: 555 AN: 5766

European-Non Finnish (NFE) AF: 0.137 AC: 151790 AN: 1111960

Other (OTH) AF: 0.143 AC: 8643 AN: 60396

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

African (AFR) AF: 0.382 AC: 15801 AN: 41414

American (AMR) AF: 0.132 AC: 2024 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.167 AC: 863 AN: 5166

South Asian (SAS) AF: 0.0990 AC: 477 AN: 4820

European-Finnish (FIN) AF: 0.126 AC: 1339 AN: 10590

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9059 AN: 67952

Other (OTH) AF: 0.174 AC: 368 AN: 2110

Alfa AF: 0.159 Hom.: 1809

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.062
DANN	Benign	0.41
PhyloP100		-2.3
PromoterAI		-0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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