8-85465362-C-T

Position:

• chr8-85465362-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000067.3(CA2):​c.125C>T​(p.Pro42Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CA2 NM_000067.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.55

Genes affected

CA2 (HGNC:1373): (carbonic anhydrase 2) The protein encoded by this gene is one of several isozymes of carbonic anhydrase, which catalyzes reversible hydration of carbon dioxide. Defects in this enzyme are associated with osteopetrosis and renal tubular acidosis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Alpha-carbonic anhydrase (size 256) in uniprot entity CAH2_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_000067.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38973215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA2	NM_000067.3	c.125C>T	p.Pro42Leu	missense_variant	2/7	ENST00000285379.10
CA2	NM_001293675.2	c.-60C>T		5_prime_UTR_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA2	ENST00000285379.10	c.125C>T	p.Pro42Leu	missense_variant	2/7	1	NM_000067.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CA2 protein function. This variant has not been reported in the literature in individuals affected with CA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 42 of the CA2 protein (p.Pro42Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.036	D
Polyphen		0.013	B
Vest4		0.32
MutPred		0.52		Loss of disorder (P = 0.0315);
MVP		0.81
MPC		0.35
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.50
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-86377591; COSMIC: COSV99035269; COSMIC: COSV99035269;