8-85480713-C-A

Variant names:

• chr8-85480713-C-A
• rs118203932
• NM_000067.3:c.707C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. 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. 15/22 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
• Publications: 6 publications found

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]

CA2 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• 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 VariationId is 915.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000067.3. 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
	CA2	NM_000067.3	MANE Select	c.707C>A	p.Pro236His	missense	Exon 7 of 7	NP_000058.1	P00918
	CA2	NM_001293675.2		c.404C>A	p.Pro135His	missense	Exon 6 of 6	NP_001280604.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA2	ENST00000285379.10	TSL:1 MANE Select	c.707C>A	p.Pro236His	missense	Exon 7 of 7	ENSP00000285379.4	P00918
	CA2	ENST00000960030.1		c.701C>A	p.Pro234His	missense	Exon 7 of 7	ENSP00000630089.1
	CA2	ENST00000520127.5	TSL:3	n.*294C>A		non_coding_transcript_exon	Exon 6 of 6	ENSP00000428443.1	E5RID5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	CARBONIC ANHYDRASE II VARIANT (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.8
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
Mutation Taster		=27/73	disease causing (ClinVar)

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