8-60226721-C-T

Position:

• chr8-60226721-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+152G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.911 in 625,520 control chromosomes in the GnomAD database, including 260,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (65894 hom., cov: 30)
  • Exomes 𝑓: 0.91 (195021 hom.)
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.911

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=-0.94).
• BP6: Variant 8-60226721-C-T is Benign according to our data. Variant chr8-60226721-C-T is described in ClinVar as [Benign]. Clinvar id is 1296082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA8	NM_004056.6	c.576+152G>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+152G>A		intron_variant		1	NM_004056.6	ENSP00000314407	P1
CA8	ENST00000524872.5	n.814+152G>A		intron_variant, non_coding_transcript_variant		1
CA8	ENST00000528666.1	n.348+152G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.929 AC: 141307 AN: 152082 Hom.: 65836 Cov.: 30

Gnomad AFR AF: 0.961

Gnomad AMI AF: 0.964

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.955

Gnomad EAS AF: 0.746

Gnomad SAS AF: 0.836

Gnomad FIN AF: 0.890

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.933

Gnomad OTH AF: 0.930

GnomAD4 exome AF: 0.905 AC: 428507 AN: 473320 Hom.: 195021 AF XY: 0.902 AC XY: 228049 AN XY: 252864

Gnomad4 AFR exome AF: 0.964

Gnomad4 AMR exome AF: 0.932

Gnomad4 ASJ exome AF: 0.953

Gnomad4 EAS exome AF: 0.714

Gnomad4 SAS exome AF: 0.833

Gnomad4 FIN exome AF: 0.892

Gnomad4 NFE exome AF: 0.933

Gnomad4 OTH exome AF: 0.915

GnomAD4 genome AF: 0.929 AC: 141426 AN: 152200 Hom.: 65894 Cov.: 30 AF XY: 0.924 AC XY: 68733 AN XY: 74384

Gnomad4 AFR AF: 0.961

Gnomad4 AMR AF: 0.936

Gnomad4 ASJ AF: 0.955

Gnomad4 EAS AF: 0.746

Gnomad4 SAS AF: 0.838

Gnomad4 FIN AF: 0.890

Gnomad4 NFE AF: 0.933

Gnomad4 OTH AF: 0.931

Alfa AF: 0.935 Hom.: 8271

Bravo AF: 0.935

Asia WGS AF: 0.815 AC: 2837 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.12
DANN	Benign	0.37

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: rs12549573; hg19: chr8-61139280;