rs149391728

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_004056.6(CA8):c.299C>T(p.Ser100Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00143 in 1,613,094 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S100P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0075 ( 15 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 13 hom. )

Consequence

CA8
NM_004056.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 5.45

Publications

6 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 -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-60266044-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 17604.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.010276198).

BP6

Variant 8-60266043-G-A is Benign according to our data. Variant chr8-60266043-G-A is described in ClinVar as Benign. ClinVar VariationId is 128539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00753 (1145/152030) while in subpopulation AFR AF = 0.026 (1078/41468). AF 95% confidence interval is 0.0247. There are 15 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA8	NM_004056.6 link	c.299C>T	p.Ser100Leu	missense_variant	Exon 3 of 9	ENST00000317995.5	NP_004047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CA8	ENST00000317995.5 link	c.299C>T	p.Ser100Leu	missense_variant	Exon 3 of 9	1	NM_004056.6	ENSP00000314407.4
CA8	ENST00000524872.5 link	n.537C>T		non_coding_transcript_exon_variant	Exon 3 of 8	1
CA8	ENST00000529918.1 link	n.476C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00752

AC:

1143

AN:

151916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0260

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00204

AC:

512

AN:

250986

AF XY:

0.00145

show subpopulations

Gnomad AFR exome

AF:

0.0266

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000794

AC:

1160

AN:

1461064

Hom.:

Cov.:

AF XY:

0.000670

AC XY:

487

AN XY:

726870

show subpopulations

African (AFR)

AF:

0.0253

AC:

848

AN:

33460

American (AMR)

AF:

0.00206

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53282

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000909

AC:

101

AN:

1111554

Other (OTH)

AF:

0.00176

AC:

106

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00753

AC:

1145

AN:

152030

Hom.:

Cov.:

AF XY:

0.00738

AC XY:

548

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0260

AC:

1078

AN:

41468

American (AMR)

AF:

0.00294

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000177

AC:

AN:

67988

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00295

Hom.:

Bravo

AF:

0.00851

ESP6500AA

AF:

0.0207

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00236

AC:

287

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jul 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Oct 12, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Benign

0.12

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.4

PhyloP100

5.4

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Benign

0.050

Sift4G

Uncertain

0.051

Polyphen

0.76

Vest4

0.14

MVP

0.43

MPC

0.60

ClinPred

0.026

GERP RS

4.7

Varity_R

0.23

gMVP

0.74

Mutation Taster

=84/16

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over