rs10216440

Variant names:

• chr8-60273163-T-C
• rs10216440
• NM_004056.6:c.292+6526A>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.292+6526A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 152,232 control chromosomes in the GnomAD database, including 53,951 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 0.84 (53951 hom., cov: 34)
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.82
• Publications: 5 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA8	NM_004056.6	c.292+6526A>G		intron_variant	Intron 2 of 8	ENST00000317995.5	NP_004047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.292+6526A>G		intron_variant	Intron 2 of 8	1	NM_004056.6	ENSP00000314407.4
CA8	ENST00000524872.5	n.530+6526A>G		intron_variant	Intron 2 of 7	1
CA8	ENST00000529918.1	n.469+6526A>G		intron_variant	Intron 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127916 AN: 152114 Hom.: 53902 Cov.: 34

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.844

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.858

Gnomad SAS AF: 0.856

Gnomad FIN AF: 0.835

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.833

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

GnomAD4 genome AF: 0.841 AC: 128025 AN: 152232 Hom.: 53951 Cov.: 34 AF XY: 0.842 AC XY: 62633 AN XY: 74428

African (AFR) AF: 0.890 AC: 36991 AN: 41546

American (AMR) AF: 0.843 AC: 12902 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2768 AN: 3470

East Asian (EAS) AF: 0.859 AC: 4449 AN: 5182

South Asian (SAS) AF: 0.856 AC: 4126 AN: 4820

European-Finnish (FIN) AF: 0.835 AC: 8843 AN: 10592

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55140 AN: 68008

Other (OTH) AF: 0.835 AC: 1765 AN: 2114

Alfa AF: 0.817 Hom.: 184670

Bravo AF: 0.843

Asia WGS AF: 0.867 AC: 3016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.031
DANN	Benign	0.60
PhyloP100		-2.8
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: rs10216440; hg19: chr8-61185722;