Genetic Variant POLA2:p.Arg167Pro (chr11-65278768-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_002689.4(POLA2):c.500G>C(p.Arg167Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

POLA2
NM_002689.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.38

Publications

0 publications found

Variant links:

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

POLA2 links:

ENSG00000285816 (HGNC:):

ENSG00000285816 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLA2	NM_002689.4	MANE Select	c.500G>C	p.Arg167Pro	missense	Exon 6 of 18	NP_002680.2
POLA2	NM_001438747.1		c.500G>C	p.Arg167Pro	missense	Exon 6 of 18	NP_001425676.1
POLA2	NM_001437761.1		c.500G>C	p.Arg167Pro	missense	Exon 6 of 18	NP_001424690.1	A0A9L9PY44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLA2	ENST00000265465.8	TSL:1 MANE Select	c.500G>C	p.Arg167Pro	missense	Exon 6 of 18	ENSP00000265465.3	Q14181-1
ENSG00000285816	ENST00000649896.1		n.500G>C		non_coding_transcript_exon	Exon 6 of 20	ENSP00000498025.1	A0A3B3ITS5
POLA2	ENST00000525924.2	TSL:5	c.500G>C	p.Arg167Pro	missense	Exon 6 of 18	ENSP00000434173.2	H0YDR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461430

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5506

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111926

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

PhyloP100

4.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.2

REVEL

Benign

0.16

Sift

Benign

0.046

Sift4G

Benign

0.063

Polyphen

1.0

Vest4

0.32

MutPred

0.67

Loss of MoRF binding (P = 0.0174)

MVP

0.32

MPC

0.28

ClinPred

0.96

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.66

gMVP

0.67

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over