8-60226760-C-T

Position:

• chr8-60226760-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004056.6(CA8):​c.576+113G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.374 in 704,372 control chromosomes in the GnomAD database, including 51,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10088 hom., cov: 31)
  • Exomes 𝑓: 0.38 (40962 hom.)
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.83

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 8-60226760-C-T is Benign according to our data. Variant chr8-60226760-C-T is described in ClinVar as [Benign]. Clinvar id is 1174236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA8	NM_004056.6	c.576+113G>A		intron_variant		ENST00000317995.5	NP_004047.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA8	ENST00000317995.5	c.576+113G>A		intron_variant		1	NM_004056.6	ENSP00000314407	P1
CA8	ENST00000524872.5	n.814+113G>A		intron_variant, non_coding_transcript_variant		1
CA8	ENST00000528666.1	n.348+113G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54133 AN: 151800 Hom.: 10076 Cov.: 31

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.435

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.358

GnomAD4 exome AF: 0.378 AC: 209085 AN: 552454 Hom.: 40962 AF XY: 0.373 AC XY: 111368 AN XY: 298300

Gnomad4 AFR exome AF: 0.262

Gnomad4 AMR exome AF: 0.485

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.243

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.417

Gnomad4 NFE exome AF: 0.398

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.357 AC: 54170 AN: 151918 Hom.: 10088 Cov.: 31 AF XY: 0.355 AC XY: 26351 AN XY: 74254

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.435

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.402

Gnomad4 OTH AF: 0.364

Alfa AF: 0.374 Hom.: 1364

Bravo AF: 0.355

Asia WGS AF: 0.287 AC: 1001 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.0080
DANN	Benign	0.62

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: rs12549574; hg19: chr8-61139319; COSMIC: COSV58771155;