dbSNP rs200613332: POLA2:p.Ala47Gly (chr11-65266642-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002689.4(POLA2):c.140C>G(p.Ala47Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

POLA2
NM_002689.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA2	NM_002689.4 link	c.140C>G	p.Ala47Gly	missense_variant	Exon 2 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.140C>G	p.Ala47Gly	missense_variant	Exon 2 of 18	1	NM_002689.4	ENSP00000265465.3		Q14181-1
ENSG00000285816	ENST00000649896.1 link	n.140C>G		non_coding_transcript_exon_variant	Exon 2 of 20			ENSP00000498025.1		A0A3B3ITS5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251478

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1461558

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000105

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140C>G (p.A47G) alteration is located in exon 2 (coding exon 2) of the POLA2 gene. This alteration results from a C to G substitution at nucleotide position 140, causing the alanine (A) at amino acid position 47 to be replaced by a glycine (G). 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

0.22

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-0.78

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.5

D;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.68

MVP

0.43

MPC

0.72

ClinPred

0.65

GERP RS

5.2

Varity_R

0.83

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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