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

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]

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 [Likely_benign]. Clinvar id 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 FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.*36-9_*36-8insT		intron_variant	Intron 8 of 8	1	NM_004056.6	ENSP00000314407.4

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

Gnomad4 AFR exome AC: 0 AN: 0

Gnomad4 AMR exome AC: 0 AN: 0

Gnomad4 ASJ exome AC: 0 AN: 0

Gnomad4 EAS exome AC: 0 AN: 0

Gnomad4 SAS exome AC: 0 AN: 0

Gnomad4 FIN exome AC: 0 AN: 0

Gnomad4 NFE exome AC: 0 AN: 0

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.0262 AC: 0.0262266 AN: 0.0262266

Gnomad4 AMR AF: 0.0159 AC: 0.0159321 AN: 0.0159321

Gnomad4 ASJ AF: 0.0118 AC: 0.0117739 AN: 0.0117739

Gnomad4 EAS AF: 0.00923 AC: 0.00922819 AN: 0.00922819

Gnomad4 SAS AF: 0.00495 AC: 0.00494761 AN: 0.00494761

Gnomad4 FIN AF: 0.0488 AC: 0.0487805 AN: 0.0487805

Gnomad4 NFE AF: 0.0222 AC: 0.0221524 AN: 0.0221524

Gnomad4 OTH AF: 0.0225 AC: 0.0224796 AN: 0.0224796

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs57677078; hg19: chr8-61102552;