11-65297219-GGG-CGA

Variant names:

• chr11-65297219-GGG-CGA
• NM_002689.4:c.1747_1749delGGGinsCGA
• POLA2 p.Gly583Arg

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_002689.4(POLA2):​c.1747_1749delGGGinsCGA​(p.Gly583Arg) 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLA2 NM_002689.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239
• Publications: 0 publications found

Genes affected

POLA2 (HGNC:30073): (DNA polymerase alpha 2, accessory subunit) Predicted to enable DNA binding activity. Involved in DNA replication, synthesis of RNA primer. Located in cytosol and nucleoplasm. Part of alpha DNA polymerase:primase complex. [provided by Alliance of Genome Resources, Apr 2022]

POLA2 Gene-Disease associations (from GenCC):

• telomere syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285816 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.0585 (below the threshold of 3.09). Trascript score misZ: 1.5804 (below the threshold of 3.09). GenCC associations: The gene is linked to telomere syndrome.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002689.4. 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
	POLA2	NM_002689.4	MANE Select	c.1747_1749delGGGinsCGA	p.Gly583Arg	missense	N/A	NP_002680.2
	POLA2	NM_001437761.1		c.*114_*116delGGGinsCGA		3_prime_UTR	Exon 18 of 18	NP_001424690.1	A0A9L9PY44
	POLA2	NM_001438747.1		c.1647+1229_1647+1231delGGGinsCGA		intron	N/A	NP_001425676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA2	ENST00000265465.8	TSL:1 MANE Select	c.1747_1749delGGGinsCGA	p.Gly583Arg	missense	N/A	ENSP00000265465.3	Q14181-1
	ENSG00000285816	ENST00000649896.1		n.1647+1229_1647+1231delGGGinsCGA		intron	N/A	ENSP00000498025.1	A0A3B3ITS5
	POLA2	ENST00000875243.1		c.1597_1599delGGGinsCGA	p.Gly533Arg	missense	N/A	ENSP00000545302.1

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		0.24

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: chr11-65064690;