8-60189993-C-CA

Position:

• chr8-60189993-C-CA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_004056.6(CA8):​c.*36-9_*36-8insT variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, 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

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA8	NM_004056.6	c.*36-9_*36-8insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000317995.5	NP_004047.3
CA8	NM_001321839.2	c.*36-9_*36-8insT		splice_polypyrimidine_tract_variant, intron_variant			NP_001308768.1
CA8	NR_135821.2	n.1212-9_1212-8insT		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.*36-9_*36-8insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004056.6	ENSP00000314407	P1

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 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

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00923

Gnomad4 SAS AF: 0.00495

Gnomad4 FIN AF: 0.0488

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.0225

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Computational scores

Source: dbNSFP v4.3

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;