8-60281611-T-G

Variant names:

• chr8-60281611-T-G
• rs10957125
• NM_004056.6:c.-464A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004056.6(CA8):​c.-464A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 148,324 control chromosomes in the GnomAD database, including 15,003 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (15003 hom., cov: 26)
• Consequence: CA8 NM_004056.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28
• Publications: 7 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-60281611-T-G is Benign according to our data. Variant chr8-60281611-T-G is described in ClinVar as Benign. ClinVar VariationId is 1275390.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA8	NM_004056.6	c.-464A>C		upstream_gene_variant		ENST00000317995.5	NP_004047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.-464A>C		upstream_gene_variant		1	NM_004056.6	ENSP00000314407.4
CA8	ENST00000524872.5	n.-226A>C		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 66069 AN: 148220 Hom.: 14981 Cov.: 26

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.381

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.438

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

GnomAD4 genome AF: 0.446 AC: 66124 AN: 148324 Hom.: 15003 Cov.: 26 AF XY: 0.445 AC XY: 32086 AN XY: 72168

African (AFR) AF: 0.563 AC: 22872 AN: 40636

American (AMR) AF: 0.380 AC: 5642 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1591 AN: 3444

East Asian (EAS) AF: 0.290 AC: 1361 AN: 4694

South Asian (SAS) AF: 0.443 AC: 2039 AN: 4598

European-Finnish (FIN) AF: 0.437 AC: 4298 AN: 9838

Middle Eastern (MID) AF: 0.434 AC: 125 AN: 288

European-Non Finnish (NFE) AF: 0.401 AC: 26861 AN: 67022

Other (OTH) AF: 0.442 AC: 915 AN: 2072

Alfa AF: 0.408 Hom.: 2434

Bravo AF: 0.437

Asia WGS AF: 0.381 AC: 1329 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.0
DANN	Benign	0.19
PhyloP100		-1.3
PromoterAI		-0.021	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10957125; hg19: chr8-61194170;