8-60222337-CAG-C

Position:

• chr8-60222337-CAG-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BA1

The NM_001321838.2(CA8):​c.757_758delCT​(p.Leu253fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 152,214 control chromosomes in the GnomAD database, including 3,935 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (3935 hom., cov: 27)
• Consequence: CA8 NM_001321838.2 frameshift
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.03

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0442 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 8-60222337-CAG-C is Benign according to our data. Variant chr8-60222337-CAG-C is described in ClinVar as [Benign]. Clinvar id is 1234590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA8	NM_004056.6	c.738+310_738+311delCT		intron_variant		ENST00000317995.5	NP_004047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.738+310_738+311delCT		intron_variant		1	NM_004056.6	ENSP00000314407.4
CA8	ENST00000524872.5	n.976+310_976+311delCT		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31424 AN: 152096 Hom.: 3940 Cov.: 27

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.346

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.306

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.206 AC: 31411 AN: 152214 Hom.: 3935 Cov.: 27 AF XY: 0.207 AC XY: 15368 AN XY: 74410

Gnomad4 AFR AF: 0.0657

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.307

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.213

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.253

Alfa AF: 0.229 Hom.: 555

Bravo AF: 0.206

Asia WGS AF: 0.240 AC: 833 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs5891755; hg19: chr8-61134896;