rs118203932

Positions:

• chr8-85480713-C-A
• chr8-85480713-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000067.3(CA2):​c.707C>A​(p.Pro236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. P236P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CA2 NM_000067.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.78

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 5 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
• PP5: Variant 8-85480713-C-A is Pathogenic according to our data. Variant chr8-85480713-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 915.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA2	NM_000067.3	c.707C>A	p.Pro236His	missense_variant	7/7	ENST00000285379.10
CA2	NM_001293675.2	c.404C>A	p.Pro135His	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA2	ENST00000285379.10	c.707C>A	p.Pro236His	missense_variant	7/7	1	NM_000067.3	P1
CA2	ENST00000520127.5	c.*294C>A		3_prime_UTR_variant, NMD_transcript_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

CARBONIC ANHYDRASE II VARIANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1983

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.7e-8	A
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.087
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.035	D
Polyphen		0.0040	B
Vest4		0.26
MutPred		0.35		Loss of glycosylation at P236 (P = 0.0227);
MVP		0.74
MPC		0.31
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.23
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

LitVar

Other links and lift over

dbSNP: rs118203932; hg19: chr8-86392942; COSMIC: COSV53407378; COSMIC: COSV53407378;