NM_004056.6:c.514-113A>G

Variant names:

• chr8-60227048-T-C
• rs60618306
• NM_004056.6:c.514-113A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004056.6(CA8):​c.514-113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 770,548 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (35 hom.)
• Consequence: CA8 NM_004056.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.892
• 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), 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-60227048-T-C is Benign according to our data. Variant chr8-60227048-T-C is described in ClinVar as Benign. ClinVar VariationId is 1266112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 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.514-113A>G		intron	N/A	NP_004047.3
	CA8	NM_001321837.2		c.514-113A>G		intron	N/A	NP_001308766.1	P35219
	CA8	NM_001321838.2		c.514-113A>G		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.514-113A>G		intron	N/A	ENSP00000314407.4	P35219
	CA8	ENST00000524872.5	TSL:1	n.752-113A>G		intron	N/A
	CA8	ENST00000943617.1		c.514-113A>G		intron	N/A	ENSP00000613676.1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2413 AN: 152002 Hom.: 73 Cov.: 32

Gnomad AFR AF: 0.0556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00864

GnomAD4 exome AF: 0.00187 AC: 1159 AN: 618428 Hom.: 35 AF XY: 0.00146 AC XY: 488 AN XY: 334174

African (AFR) AF: 0.0533 AC: 912 AN: 17112

American (AMR) AF: 0.00269 AC: 101 AN: 37528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20210

East Asian (EAS) AF: 0.00 AC: 0 AN: 33748

South Asian (SAS) AF: 0.0000759 AC: 5 AN: 65872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49746

Middle Eastern (MID) AF: 0.00162 AC: 4 AN: 2470

European-Non Finnish (NFE) AF: 0.0000695 AC: 25 AN: 359968

Other (OTH) AF: 0.00352 AC: 112 AN: 31774

GnomAD4 genome AF: 0.0159 AC: 2415 AN: 152120 Hom.: 73 Cov.: 32 AF XY: 0.0158 AC XY: 1177 AN XY: 74368

African (AFR) AF: 0.0554 AC: 2300 AN: 41480

American (AMR) AF: 0.00563 AC: 86 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67994

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.0147 Hom.: 5

Bravo AF: 0.0177

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.7
DANN	Benign	0.73
PhyloP100		0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs60618306; hg19: chr8-61139607;