dbSNP rs6984526: CA8:c.418-4793G>A (chr8-60237172-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004056.6(CA8):c.418-4793G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 151,996 control chromosomes in the GnomAD database, including 21,703 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.53 ( 21703 hom., cov: 32)

Consequence

CA8
NM_004056.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.608

Publications

4 publications found

Variant links:

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]

CA8 Gene-Disease associations (from GenCC):

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
cerebellar ataxia
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
cerebellar ataxia, intellectual disability, and dysequilibrium
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CA8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA8	NM_004056.6 link	c.418-4793G>A		intron_variant	Intron 3 of 8	ENST00000317995.5	NP_004047.3	P35219

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5 link	c.418-4793G>A		intron_variant	Intron 3 of 8	1	NM_004056.6	ENSP00000314407.4		P35219
CA8	ENST00000524872.5 link	n.656-4793G>A		intron_variant	Intron 3 of 7	1

Frequencies

GnomAD3 genomes

AF:

0.529

AC:

80321

AN:

151878

Hom.:

21670

Cov.:

show subpopulations

Gnomad AFR

AF:

0.614

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.444

Gnomad ASJ

AF:

0.627

Gnomad EAS

AF:

0.363

Gnomad SAS

AF:

0.534

Gnomad FIN

AF:

0.457

Gnomad MID

AF:

0.547

Gnomad NFE

AF:

0.515

Gnomad OTH

AF:

0.533

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.529

AC:

80399

AN:

151996

Hom.:

21703

Cov.:

AF XY:

0.525

AC XY:

38990

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.614

AC:

25455

AN:

41450

American (AMR)

AF:

0.444

AC:

6774

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.627

AC:

2174

AN:

3468

East Asian (EAS)

AF:

0.363

AC:

1875

AN:

5162

South Asian (SAS)

AF:

0.535

AC:

2576

AN:

4812

European-Finnish (FIN)

AF:

0.457

AC:

4822

AN:

10544

Middle Eastern (MID)

AF:

0.544

AC:

160

AN:

294

European-Non Finnish (NFE)

AF:

0.515

AC:

34995

AN:

67970

Other (OTH)

AF:

0.530

AC:

1121

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1917

3834

5750

7667

9584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

696

1392

2088

2784

3480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.520

Hom.:

82923

Bravo

AF:

0.528

Asia WGS

AF:

0.473

AC:

1646

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.8

(source)

DANN

Benign

0.74

PhyloP100

-0.61

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over