8-60222337-CAG-C

Variant names:

• chr8-60222337-CAG-C
• rs5891755
• NM_004056.6:c.738+310_738+311delCT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BA1

The NM_001321838.2(CA8):​c.757_758delCT​(p.Leu253GlyfsTer55) 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
• 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.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321838.2. 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.738+310_738+311delCT		intron	N/A	NP_004047.3
	CA8	NM_001321838.2		c.757_758delCT	p.Leu253GlyfsTer55	frameshift	Exon 8 of 9	NP_001308767.1
	CA8	NM_001321837.2		c.738+310_738+311delCT		intron	N/A	NP_001308766.1	P35219

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA8	ENST00000317995.5	TSL:1 MANE Select	c.738+310_738+311delCT		intron	N/A	ENSP00000314407.4	P35219
	CA8	ENST00000524872.5	TSL:1	n.976+310_976+311delCT		intron	N/A
	CA8	ENST00000943617.1		c.738+310_738+311delCT		intron	N/A	ENSP00000613676.1

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

African (AFR) AF: 0.0657 AC: 2729 AN: 41554

American (AMR) AF: 0.237 AC: 3621 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1347 AN: 3460

East Asian (EAS) AF: 0.307 AC: 1587 AN: 5176

South Asian (SAS) AF: 0.225 AC: 1087 AN: 4826

European-Finnish (FIN) AF: 0.213 AC: 2252 AN: 10586

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17851 AN: 68006

Other (OTH) AF: 0.253 AC: 536 AN: 2116

Alfa AF: 0.229 Hom.: 555

Bravo AF: 0.206

Asia WGS AF: 0.240 AC: 833 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5891755; hg19: chr8-61134896;