chr8-60226721-C-T

Variant names:

• chr8-60226721-C-T
• rs12549573
• NM_004056.6:c.576+152G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004056.6. 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.576+152G>A		intron	N/A	NP_004047.3
	CA8	NM_001321837.2		c.576+152G>A		intron	N/A	NP_001308766.1	P35219
	CA8	NM_001321838.2		c.576+152G>A		intron	N/A	NP_001308767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA8	ENST00000317995.5	TSL:1 MANE Select	c.576+152G>A		intron	N/A	ENSP00000314407.4	P35219
	CA8	ENST00000524872.5	TSL:1	n.814+152G>A		intron	N/A
	CA8	ENST00000943617.1		c.576+152G>A		intron	N/A	ENSP00000613676.1

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

African (AFR) AF: 0.964 AC: 11991 AN: 12442

American (AMR) AF: 0.932 AC: 20342 AN: 21830

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 14152 AN: 14846

East Asian (EAS) AF: 0.714 AC: 21457 AN: 30064

South Asian (SAS) AF: 0.833 AC: 39214 AN: 47064

European-Finnish (FIN) AF: 0.892 AC: 38762 AN: 43468

Middle Eastern (MID) AF: 0.900 AC: 1959 AN: 2176

European-Non Finnish (NFE) AF: 0.933 AC: 256926 AN: 275514

Other (OTH) AF: 0.915 AC: 23704 AN: 25916

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

African (AFR) AF: 0.961 AC: 39924 AN: 41542

American (AMR) AF: 0.936 AC: 14310 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.955 AC: 3316 AN: 3472

East Asian (EAS) AF: 0.746 AC: 3854 AN: 5166

South Asian (SAS) AF: 0.838 AC: 4029 AN: 4810

European-Finnish (FIN) AF: 0.890 AC: 9414 AN: 10576

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.933 AC: 63469 AN: 68024

Other (OTH) AF: 0.931 AC: 1970 AN: 2116

Alfa AF: 0.926 Hom.: 18985

Bravo AF: 0.935

Asia WGS AF: 0.815 AC: 2837 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.12
DANN	Benign	0.37
PhyloP100		-0.91
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: rs12549573; hg19: chr8-61139280;