NM_004056.6:c.449T>G

Variant names:

• chr8-60232348-A-C
• NM_004056.6:c.449T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004056.6(CA8):​c.449T>G​(p.Phe150Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CA8 NM_004056.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.07

Genes affected

CA8 (HGNC:1382): (carbonic anhydrase 8) The protein encoded by this gene was initially named CA-related protein because of sequence similarity to other known carbonic anhydrase genes. However, the gene product lacks carbonic anhydrase activity (i.e., the reversible hydration of carbon dioxide). The gene product continues to carry a carbonic anhydrase designation based on clear sequence identity to other members of the carbonic anhydrase gene family. The absence of CA8 gene transcription in the cerebellum of the lurcher mutant in mice with a neurologic defect suggests an important role for this acatalytic form. Mutations in this gene are associated with cerebellar ataxia, mental retardation, and dysequilibrium syndrome 3 (CMARQ3). Polymorphisms in this gene are associated with osteoporosis, and overexpression of this gene in osteosarcoma cells suggests an oncogenic role. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA8	NM_004056.6	c.449T>G	p.Phe150Cys	missense_variant	Exon 4 of 9	ENST00000317995.5	NP_004047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.449T>G	p.Phe150Cys	missense_variant	Exon 4 of 9	1	NM_004056.6	ENSP00000314407.4
CA8	ENST00000524872.5	n.687T>G		non_coding_transcript_exon_variant	Exon 4 of 8	1
CA8	ENST00000528666.1	n.221T>G		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.67
MutPred		0.93		Loss of glycosylation at S152 (P = 0.2006);
MVP		0.39
MPC		0.70
ClinPred		0.99	D
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.88

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: chr8-61144907;