15-63338888-C-G

Position:

• chr15-63338888-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001218.5(CA12):​c.805G>C​(p.Glu269Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: CA12 NM_001218.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.21

Genes affected

CA12 (HGNC:1371): (carbonic anhydrase 12) 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. This gene product is a type I membrane protein that is highly expressed in normal tissues, such as kidney, colon and pancreas, and has been found to be overexpressed in 10% of clear cell renal carcinomas. Three transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2014]

LOC124903506 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20620504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA12	NM_001218.5	c.805G>C	p.Glu269Gln	missense_variant	8/11	ENST00000178638.8	NP_001209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA12	ENST00000178638.8	c.805G>C	p.Glu269Gln	missense_variant	8/11	1	NM_001218.5	ENSP00000178638.3
CA12	ENST00000344366.7	c.805G>C	p.Glu269Gln	missense_variant	8/10	1		ENSP00000343088.3
CA12	ENST00000422263.2	c.625G>C	p.Glu209Gln	missense_variant	7/9	2		ENSP00000403028.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461890 Hom.: 1 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2022

The c.805G>C (p.E269Q) alteration is located in exon 8 (coding exon 8) of the CA12 gene. This alteration results from a G to C substitution at nucleotide position 805, causing the glutamic acid (E) at amino acid position 269 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.77	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.030	B;B;B
Vest4		0.38
MVP		0.76
MPC		0.26
ClinPred		0.67	D
GERP RS		5.8
Varity_R		0.32
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1179428839; hg19: chr15-63631087;