11-65267517-G-T

Variant names:

• chr11-65267517-G-T
• NM_002689.4:c.245G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002689.4(POLA2):​c.245G>T​(p.Cys82Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLA2 NM_002689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.496

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]

ENSG00000285816 (HGNC:):

ACMG classification

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=0.0566642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLA2	NM_002689.4	c.245G>T	p.Cys82Phe	missense_variant	Exon 3 of 18	ENST00000265465.8	NP_002680.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLA2	ENST00000265465.8	c.245G>T	p.Cys82Phe	missense_variant	Exon 3 of 18	1	NM_002689.4	ENSP00000265465.3
ENSG00000285816	ENST00000649896.1	n.245G>T		non_coding_transcript_exon_variant	Exon 3 of 20			ENSP00000498025.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460206 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726390

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245G>T (p.C82F) alteration is located in exon 3 (coding exon 3) of the POLA2 gene. This alteration results from a G to T substitution at nucleotide position 245, causing the cysteine (C) at amino acid position 82 to be replaced by a phenylalanine (F). 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	0.069
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.6
DANN	Benign	0.86
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.011
Sift	Benign	0.73	T;T
Sift4G	Benign	0.56	T;D
Polyphen		0.0	B;B
Vest4		0.15
MutPred		0.32		Loss of methylation at K83 (P = 0.0681);.;
MVP		0.055
MPC		0.27
ClinPred		0.091	T
GERP RS		2.7
Varity_R		0.036
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-65034988;