8-85328605-GC-AT

Variant names:

• chr8-85328605-GC-AT
• NM_001128831.4:c.740_741delGCinsAT
• CA1 p.Arg247His

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1

The NM_001128831.4(CA1):​c.740_741delGCinsAT​(p.Arg247His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CA1 NM_001128831.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_001128831.4 (CA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128831.4. 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
	CA1	NM_001128831.4	MANE Select	c.740_741delGCinsAT	p.Arg247His	missense	N/A	NP_001122303.1	P00915
	CA1	NM_001128829.4		c.740_741delGCinsAT	p.Arg247His	missense	N/A	NP_001122301.1	P00915
	CA1	NM_001128830.4		c.740_741delGCinsAT	p.Arg247His	missense	N/A	NP_001122302.1	P00915

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA1	ENST00000523022.6	TSL:1 MANE Select	c.740_741delGCinsAT	p.Arg247His	missense	N/A	ENSP00000429798.1	P00915
	CA1	ENST00000523953.5	TSL:1	c.740_741delGCinsAT	p.Arg247His	missense	N/A	ENSP00000430656.1	P00915
	CA1	ENST00000517618.5	TSL:1	c.740_741delGCinsAT	p.Arg247His	missense	N/A	ENSP00000430861.1	E5RHP7

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-86240834;