8-60226760-C-T

Variant names:

• chr8-60226760-C-T
• rs12549574
• NM_004056.6:c.576+113G>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+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
• Publications: 2 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), PanelApp Australia, 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=-0.99).
• BP6: Variant 8-60226760-C-T is Benign according to our data. Variant chr8-60226760-C-T is described in ClinVar as Benign. ClinVar VariationId 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.

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+113G>A		intron	N/A	NP_004047.3
	CA8	NM_001321837.2		c.576+113G>A		intron	N/A	NP_001308766.1	P35219
	CA8	NM_001321838.2		c.576+113G>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+113G>A		intron	N/A	ENSP00000314407.4	P35219
	CA8	ENST00000524872.5	TSL:1	n.814+113G>A		intron	N/A
	CA8	ENST00000943617.1		c.576+113G>A		intron	N/A	ENSP00000613676.1

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

African (AFR) AF: 0.262 AC: 3889 AN: 14838

American (AMR) AF: 0.485 AC: 15807 AN: 32618

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 6092 AN: 18934

East Asian (EAS) AF: 0.243 AC: 7658 AN: 31464

South Asian (SAS) AF: 0.312 AC: 18666 AN: 59864

European-Finnish (FIN) AF: 0.417 AC: 19829 AN: 47544

Middle Eastern (MID) AF: 0.360 AC: 1230 AN: 3418

European-Non Finnish (NFE) AF: 0.398 AC: 125109 AN: 314222

Other (OTH) AF: 0.366 AC: 10805 AN: 29552

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

African (AFR) AF: 0.260 AC: 10781 AN: 41418

American (AMR) AF: 0.435 AC: 6639 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1122 AN: 3470

East Asian (EAS) AF: 0.215 AC: 1107 AN: 5150

South Asian (SAS) AF: 0.298 AC: 1437 AN: 4822

European-Finnish (FIN) AF: 0.422 AC: 4444 AN: 10534

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.402 AC: 27340 AN: 67944

Other (OTH) AF: 0.364 AC: 767 AN: 2108

Alfa AF: 0.374 Hom.: 1364

Bravo AF: 0.355

Asia WGS AF: 0.287 AC: 1001 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.99
CADD	Benign	0.0080
DANN	Benign	0.62
PhyloP100		-1.8
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: rs12549574; hg19: chr8-61139319; COSMIC: COSV58771155;