chr11-65262369-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_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. 18/24 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

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 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.

BP4

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

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.77A>G	p.Lys26Arg	missense splice_region	Exon 1 of 18	NP_002680.2
POLA2	NM_001438747.1		c.77A>G	p.Lys26Arg	missense splice_region	Exon 1 of 18	NP_001425676.1
POLA2	NM_001437761.1		c.77A>G	p.Lys26Arg	missense splice_region	Exon 1 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.77A>G	p.Lys26Arg	missense splice_region	Exon 1 of 18	ENSP00000265465.3	Q14181-1
ENSG00000285816	ENST00000649896.1		n.77A>G		splice_region non_coding_transcript_exon	Exon 1 of 20	ENSP00000498025.1	A0A3B3ITS5
POLA2	ENST00000525924.2	TSL:5	c.77A>G	p.Lys26Arg	missense splice_region	Exon 1 of 18	ENSP00000434173.2	H0YDR7

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

GnomAD2 exomes

AF:

0.000162

AC:

AN:

247444

AF XY:

0.000142

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 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

African (AFR)

AF:

0.000958

AC:

AN:

33404

American (AMR)

AF:

0.000157

AC:

AN:

44630

Ashkenazi Jewish (ASJ)

AF:

0.000383

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.0000349

AC:

AN:

85982

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000963

AC:

107

AN:

1110864

Other (OTH)

AF:

0.000249

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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

AF:

0.000296

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41552

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000430

Hom.:

Bravo

AF:

0.000397

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000297

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

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

PhyloP100

1.1

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

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.27

gMVP

0.33

Mutation Taster

=76/24

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over