11-65278768-G-A

Variant names:

• chr11-65278768-G-A
• rs377028201
• NM_002689.4:c.500G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_002689.4(POLA2):​c.500G>A​(p.Arg167Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,613,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: POLA2 NM_002689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.38
• Publications: 1 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.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24286306).

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.500G>A	p.Arg167Gln	missense	Exon 6 of 18	NP_002680.2
	POLA2	NM_001438747.1		c.500G>A	p.Arg167Gln	missense	Exon 6 of 18	NP_001425676.1
	POLA2	NM_001437761.1		c.500G>A	p.Arg167Gln	missense	Exon 6 of 18	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.500G>A	p.Arg167Gln	missense	Exon 6 of 18	ENSP00000265465.3	Q14181-1
	ENSG00000285816	ENST00000649896.1		n.500G>A		non_coding_transcript_exon	Exon 6 of 20	ENSP00000498025.1	A0A3B3ITS5
	POLA2	ENST00000525924.2	TSL:5	c.500G>A	p.Arg167Gln	missense	Exon 6 of 18	ENSP00000434173.2	H0YDR7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461430 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727020

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111926

Other (OTH) AF: 0.0000166 AC: 1 AN: 60354

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41398

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.12
Sift	Benign	0.20	T
Sift4G	Benign	0.26	T
Polyphen		0.94	P
Vest4		0.20
MVP		0.24
MPC		0.21
ClinPred		0.69	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.43
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs377028201; hg19: chr11-65046239; COSMIC: COSV55481941; COSMIC: COSV55481941;