8-60189993-C-CA

Variant names:

• chr8-60189993-C-CA
• rs57677078
• NM_004056.6:c.*36-9dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004056.6(CA8):​c.*36-9dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 109,258 control chromosomes in the GnomAD database, including 23 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (23 hom., cov: 26)
  • Failed GnomAD Quality Control
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Benign/Likely benign no assertion criteria provided B:2
• 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 -9 ACMG points.

• BP6: Variant 8-60189993-C-CA is Benign according to our data. Variant chr8-60189993-C-CA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1285068.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.023 (2517/109258) while in subpopulation AFR AF = 0.0262 (913/34812). AF 95% confidence interval is 0.0248. There are 23 homozygotes in GnomAd4. There are 1244 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.*36-9dupT		intron	N/A	NP_004047.3
	CA8	NM_001321839.2		c.*36-9dupT		intron	N/A	NP_001308768.1
	CA8	NR_135821.2		n.1212-9dupT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA8	ENST00000317995.5	TSL:1 MANE Select	c.*36-9_*36-8insT		intron	N/A	ENSP00000314407.4	P35219
	CA8	ENST00000943617.1		c.*36-12_*36-11insT		intron	N/A	ENSP00000613676.1
	CA8	ENST00000943619.1		c.*36-9_*36-8insT		intron	N/A	ENSP00000613678.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 2518 AN: 109218 Hom.: 23 Cov.: 26

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00662

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00918

Gnomad SAS AF: 0.00492

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0327

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0227

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0230 AC: 2517 AN: 109258 Hom.: 23 Cov.: 26 AF XY: 0.0238 AC XY: 1244 AN XY: 52252

African (AFR) AF: 0.0262 AC: 913 AN: 34812

American (AMR) AF: 0.0159 AC: 154 AN: 9666

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 30 AN: 2548

East Asian (EAS) AF: 0.00923 AC: 33 AN: 3576

South Asian (SAS) AF: 0.00495 AC: 17 AN: 3436

European-Finnish (FIN) AF: 0.0488 AC: 284 AN: 5822

Middle Eastern (MID) AF: 0.0253 AC: 5 AN: 198

European-Non Finnish (NFE) AF: 0.0222 AC: 1044 AN: 47128

Other (OTH) AF: 0.0225 AC: 33 AN: 1468

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;