8-85477187-C-G

Variant names:

• chr8-85477187-C-G
• rs369229469
• NM_000067.3:c.575C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000067.3(CA2):​c.575C>G​(p.Thr192Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T192I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CA2 NM_000067.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 5 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.575C>G	p.Thr192Ser	missense	Exon 6 of 7	NP_000058.1	P00918
	CA2	NM_001293675.2		c.272C>G	p.Thr91Ser	missense	Exon 5 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.575C>G	p.Thr192Ser	missense	Exon 6 of 7	ENSP00000285379.4	P00918
	CA2	ENST00000960030.1		c.569C>G	p.Thr190Ser	missense	Exon 6 of 7	ENSP00000630089.1
	CA2	ENST00000520127.5	TSL:3	n.*162C>G		non_coding_transcript_exon	Exon 5 of 6	ENSP00000428443.1	E5RID5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251448 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.065	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.016	D
Polyphen		0.060	B
Vest4		0.49
MutPred		0.63		Gain of phosphorylation at S187 (P = 0.1381)
MVP		0.91
MPC		0.84
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.85
gMVP		0.69
Mutation Taster		=46/54	disease causing

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: rs369229469; hg19: chr8-86389416;