chr8-60192640-T-C

Variant names:

• chr8-60192640-T-C
• rs10098647
• NM_004056.6:c.*36-2655A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004056.6(CA8):​c.*36-2655A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,914 control chromosomes in the GnomAD database, including 17,569 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 0.47 (17569 hom., cov: 32)
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 9 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA8	NM_004056.6	c.*36-2655A>G		intron_variant	Intron 8 of 8	ENST00000317995.5	NP_004047.3
CA8	NM_001321839.2	c.*36-2655A>G		intron_variant	Intron 7 of 7		NP_001308768.1
CA8	NR_135821.2	n.1212-2655A>G		intron_variant	Intron 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.*36-2655A>G		intron_variant	Intron 8 of 8	1	NM_004056.6	ENSP00000314407.4

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70741 AN: 151794 Hom.: 17542 Cov.: 32

Gnomad AFR AF: 0.641

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.580

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.478

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

GnomAD4 genome AF: 0.466 AC: 70815 AN: 151914 Hom.: 17569 Cov.: 32 AF XY: 0.467 AC XY: 34662 AN XY: 74224

African (AFR) AF: 0.641 AC: 26561 AN: 41428

American (AMR) AF: 0.371 AC: 5658 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 1823 AN: 3466

East Asian (EAS) AF: 0.484 AC: 2494 AN: 5156

South Asian (SAS) AF: 0.494 AC: 2371 AN: 4802

European-Finnish (FIN) AF: 0.400 AC: 4204 AN: 10514

Middle Eastern (MID) AF: 0.562 AC: 164 AN: 292

European-Non Finnish (NFE) AF: 0.385 AC: 26196 AN: 67982

Other (OTH) AF: 0.477 AC: 1007 AN: 2112

Alfa AF: 0.418 Hom.: 36389

Bravo AF: 0.470

Asia WGS AF: 0.497 AC: 1724 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.57
PhyloP100		0.014
Mutation Taster		=100/0	polymorphism (auto)

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: rs10098647; hg19: chr8-61105199;