11-65262368-AAA-CGC

Variant names:

• chr11-65262368-AAA-CGC
• NM_002689.4:c.76_78delAAAinsCGC
• POLA2 p.Lys26Arg

Variant summary

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

The NM_002689.4(POLA2):​c.76_78delAAAinsCGC​(p.Lys26Arg) variant causes a missense, splice region 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 Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLA2 NM_002689.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49
• 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.76_78delAAAinsCGC	p.Lys26Arg	missense splice_region	N/A	NP_002680.2
	POLA2	NM_001438747.1		c.76_78delAAAinsCGC	p.Lys26Arg	missense splice_region	N/A	NP_001425676.1
	POLA2	NM_001437761.1		c.76_78delAAAinsCGC	p.Lys26Arg	missense splice_region	N/A	NP_001424690.1	A0A9L9PY44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA2	ENST00000265465.8	TSL:1 MANE Select	c.76_78delAAAinsCGC	p.Lys26Arg	missense splice_region	N/A	ENSP00000265465.3	Q14181-1
	ENSG00000285816	ENST00000649896.1		n.76_78delAAAinsCGC		splice_region non_coding_transcript_exon	Exon 1 of 20	ENSP00000498025.1	A0A3B3ITS5
	POLA2	ENST00000525924.2	TSL:5	c.76_78delAAAinsCGC	p.Lys26Arg	missense splice_region	N/A	ENSP00000434173.2	H0YDR7

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		2.5

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: chr11-65029839;