chr11-65266691-C-G

Variant names:

• chr11-65266691-C-G
• NM_002689.4:c.189C>G

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.189C>G​(p.Asn63Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLA2 NM_002689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.115
• Publications: 0 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=0.08825943).

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.189C>G	p.Asn63Lys	missense	Exon 2 of 18	NP_002680.2
	POLA2	NM_001438747.1		c.189C>G	p.Asn63Lys	missense	Exon 2 of 18	NP_001425676.1
	POLA2	NM_001437761.1		c.189C>G	p.Asn63Lys	missense	Exon 2 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.189C>G	p.Asn63Lys	missense	Exon 2 of 18	ENSP00000265465.3	Q14181-1
	ENSG00000285816	ENST00000649896.1		n.189C>G		non_coding_transcript_exon	Exon 2 of 20	ENSP00000498025.1	A0A3B3ITS5
	POLA2	ENST00000525924.2	TSL:5	c.189C>G	p.Asn63Lys	missense	Exon 2 of 18	ENSP00000434173.2	H0YDR7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.12
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.087
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
Polyphen		0.0020	B
Vest4		0.22
MutPred		0.62		Gain of ubiquitination at N63 (P = 0.0121)
MVP		0.11
MPC		0.20
ClinPred		0.061	T
GERP RS		-0.037
PromoterAI		0.0097	Neutral
Varity_R		0.15
gMVP		0.12
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

hg19: chr11-65034162;