8-85333605-AGT-A

Variant names:

• chr8-85333605-AGT-A
• rs768769200
• NM_001128831.4:c.368_369delAC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001128831.4(CA1):​c.368_369delAC​(p.His123LeufsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000412 in 1,457,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CA1 NM_001128831.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48

Genes affected

CA1 (HGNC:1368): (carbonic anhydrase 1) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. This CA1 gene is closely linked to the CA2 and CA3 genes on chromosome 8. It encodes a cytosolic protein that is found at the highest level in erythrocytes. Allelic variants of this gene have been described in some populations. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA1	NM_001128831.4	c.368_369delAC	p.His123LeufsTer11	frameshift_variant	Exon 5 of 8	ENST00000523022.6	NP_001122303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA1	ENST00000523022.6	c.368_369delAC	p.His123LeufsTer11	frameshift_variant	Exon 5 of 8	1	NM_001128831.4	ENSP00000429798.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250342 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457148 Hom.: 0 AF XY: 0.00000552 AC XY: 4 AN XY: 725168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal tubular acidosis;C0035579:Rickets;C0220981:Metabolic acidosis Uncertain:1

Nov 09, 2019

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A role of this CA1 gene in renal tubular acidosis was suggested earlier, however no disorder has been associated with this gene till date (Shapira et al. J Clin Invest 1974). Another gene of this family (CA2) is known to cause autosomal recessive osteopetrosis with renal tubular acidosis (MIM#259730). The c.368_369del variant is present in publicly available databases like Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP only in heterozygous state (minor allele frequency < 0.00001). The variant is not present in our in-house exome database. The variant was not reported to OMIM, ClinVar and Human Genome Mutation Database (HGMD) in any other affected individuals. In-silico pathogenicity prediction programs like MutationTaster2, CADD etc. predicted this variant as likely deleterious. -

Computational scores

Source: dbNSFP v4.3

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: rs768769200; hg19: chr8-86245834;