9-35675868-G-A

Variant names:

• chr9-35675868-G-A
• rs199516419
• NM_001216.3:c.541G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001216.3(CA9):​c.541G>A​(p.Glu181Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,606,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: CA9 NM_001216.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0450
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018421412).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	NM_001216.3	MANE Select	c.541G>A	p.Glu181Lys	missense	Exon 3 of 11	NP_001207.2	Q16790

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA9	ENST00000378357.9	TSL:1 MANE Select	c.541G>A	p.Glu181Lys	missense	Exon 3 of 11	ENSP00000367608.4	Q16790
	CA9	ENST00000903367.1		c.541G>A	p.Glu181Lys	missense	Exon 3 of 12	ENSP00000573426.1
	CA9	ENST00000903366.1		c.511G>A	p.Glu171Lys	missense	Exon 2 of 10	ENSP00000573425.1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000103 AC: 24 AN: 233144 AF XY: 0.0000853

Gnomad AFR exome AF: 0.00153

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000345

GnomAD4 exome AF: 0.0000688 AC: 100 AN: 1453964 Hom.: 0 Cov.: 33 AF XY: 0.0000567 AC XY: 41 AN XY: 723564

African (AFR) AF: 0.00263 AC: 88 AN: 33440

American (AMR) AF: 0.0000449 AC: 2 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46776

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111338

Other (OTH) AF: 0.0000830 AC: 5 AN: 60252

GnomAD4 genome AF: 0.000446 AC: 68 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74472

African (AFR) AF: 0.00161 AC: 67 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.000514

ExAC AF: 0.000102 AC: 12

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.28	N
PhyloP100		-0.045
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.19
Sift	Benign	0.14	T
Sift4G	Benign	0.31	T
Polyphen		0.89	P
Vest4		0.26
MVP		0.34
MPC		0.22
ClinPred		0.069	T
GERP RS		-4.0
Varity_R		0.23
gMVP		0.53
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs199516419; hg19: chr9-35675865;