8-60189993-CAAAAA-CAAA

Variant names:

• chr8-60189993-CAA-C
• rs57677078
• NM_004056.6:c.*36-10_*36-9delTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_004056.6(CA8):​c.*36-10_*36-9delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 109,168 control chromosomes in the GnomAD database, including 75 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.026 (75 hom., cov: 26)
  • Failed GnomAD Quality Control
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153
• Publications: 0 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), 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0702 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004056.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA8	NM_004056.6	MANE Select	c.*36-10_*36-9delTT		intron	N/A	NP_004047.3
	CA8	NM_001321839.2		c.*36-10_*36-9delTT		intron	N/A	NP_001308768.1
	CA8	NR_135821.2		n.1212-10_1212-9delTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA8	ENST00000317995.5	TSL:1 MANE Select	c.*36-10_*36-9delTT		intron	N/A	ENSP00000314407.4	P35219
	CA8	ENST00000943617.1		c.*36-13_*36-12delTT		intron	N/A	ENSP00000613676.1
	CA8	ENST00000943619.1		c.*36-10_*36-9delTT		intron	N/A	ENSP00000613678.1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 2850 AN: 109126 Hom.: 76 Cov.: 26

Gnomad AFR AF: 0.0723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.000393

Gnomad EAS AF: 0.00195

Gnomad SAS AF: 0.0217

Gnomad FIN AF: 0.00502

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0138

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

GnomAD4 genome AF: 0.0262 AC: 2865 AN: 109168 Hom.: 75 Cov.: 26 AF XY: 0.0268 AC XY: 1397 AN XY: 52200

African (AFR) AF: 0.0726 AC: 2525 AN: 34802

American (AMR) AF: 0.0151 AC: 146 AN: 9664

Ashkenazi Jewish (ASJ) AF: 0.000393 AC: 1 AN: 2544

East Asian (EAS) AF: 0.00196 AC: 7 AN: 3576

South Asian (SAS) AF: 0.0218 AC: 75 AN: 3440

European-Finnish (FIN) AF: 0.00502 AC: 29 AN: 5776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 196

European-Non Finnish (NFE) AF: 0.00130 AC: 61 AN: 47100

Other (OTH) AF: 0.0143 AC: 21 AN: 1466

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs57677078; hg19: chr8-61102552;