8-85477174-T-A

Variant names:

• chr8-85477174-T-A
• rs703
• NM_000067.3:c.562T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000067.3(CA2):​c.562T>A​(p.Leu188Met) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L188L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CA2 NM_000067.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 25 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25546736).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA2	NM_000067.3	c.562T>A	p.Leu188Met	missense_variant	Exon 6 of 7	ENST00000285379.10	NP_000058.1
CA2	NM_001293675.2	c.259T>A	p.Leu87Met	missense_variant	Exon 5 of 6		NP_001280604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA2	ENST00000285379.10	c.562T>A	p.Leu188Met	missense_variant	Exon 6 of 7	1	NM_000067.3	ENSP00000285379.4
CA2	ENST00000520127.5	n.*149T>A		non_coding_transcript_exon_variant	Exon 5 of 6	3		ENSP00000428443.1
CA2	ENST00000520127.5	n.*149T>A		3_prime_UTR_variant	Exon 5 of 6	3		ENSP00000428443.1
CA2	ENST00000522742.1	n.*336T>A		downstream_gene_variant		3		ENSP00000428947.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 47

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.8
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		-0.062
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.23
Sift	Benign	0.19	T
Sift4G	Benign	0.22	T
Polyphen		0.76	P
Vest4		0.28
MutPred		0.47		Loss of catalytic residue at L188 (P = 0.0648);
MVP		0.69
MPC		0.58
ClinPred		0.42	T
GERP RS		-6.0
Varity_R		0.49
gMVP		0.50
Mutation Taster		=85/15	polymorphism

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: rs703; hg19: chr8-86389403;