Genetic Variant POLA2:p.Lys26Arg (chr11-65262369-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002689.4(POLA2):c.77A>G(p.Lys26Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,612,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

POLA2
NM_002689.4 missense, splice_region

Scores

Splicing: ADA: 0.0003848

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

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 links:

ENSG00000285816 (HGNC:):

ENSG00000285816 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036288947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA2	NM_002689.4 link	c.77A>G	p.Lys26Arg	missense_variant, splice_region_variant	Exon 1 of 18	ENST00000265465.8	NP_002680.2	Q14181-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLA2	ENST00000265465.8 link	c.77A>G	p.Lys26Arg	missense_variant, splice_region_variant	Exon 1 of 18	1	NM_002689.4	ENSP00000265465.3		Q14181-1
ENSG00000285816	ENST00000649896.1 link	n.77A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 20			ENSP00000498025.1		A0A3B3ITS5

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000162

AC:

AN:

247444

Hom.:

AF XY:

0.000142

AC XY:

AN XY:

134042

show subpopulations

Gnomad AFR exome

AF:

0.000698

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000300

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000143

Gnomad OTH exome

AF:

0.000497

GnomAD4 exome

AF:

0.000127

AC:

185

AN:

1460050

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

726228

show subpopulations

Gnomad4 AFR exome

AF:

0.000958

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000963

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000296

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.000397

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.77A>G (p.K26R) alteration is located in exon 1 (coding exon 1) of the POLA2 gene. This alteration results from a A to G substitution at nucleotide position 77, causing the lysine (K) at amino acid position 26 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.26

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.67

M_CAP

Benign

0.0083

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

REVEL

Benign

0.097

Sift

Uncertain

0.024

Sift4G

Uncertain

0.024

Polyphen

0.21

Vest4

0.17

MVP

0.26

MPC

0.20

ClinPred

0.030

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.27

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00038

dbscSNV1_RF

Benign

0.0060

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over