rs61733782

Variant names:

• chr17-64480312-G-A
• rs61733782
• NM_007215.4:c.1269C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007215.4(POLG2):​c.1269C>T​(p.Ser423Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,572,444 control chromosomes in the GnomAD database, including 3,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (638 hom., cov: 32)
  • Exomes 𝑓: 0.060 (3018 hom.)
• Consequence: POLG2 NM_007215.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.440
• Publications: 14 publications found

Genes affected

POLG2 (HGNC:9180): (DNA polymerase gamma 2, accessory subunit) This gene encodes the processivity subunit of the mitochondrial DNA polymerase gamma. The encoded protein forms a heterotrimer containing one catalytic subunit and two processivity subunits. This protein enhances DNA binding and promotes processive DNA synthesis. Mutations in this gene result in autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions.[provided by RefSeq, Sep 2009]

MILR1 (HGNC:27570): (mast cell immunoglobulin like receptor 1) Predicted to enable transmembrane signaling receptor activity. Predicted to be involved in several processes, including cell-cell adhesion via plasma-membrane adhesion molecules; mast cell degranulation; and negative regulation of mast cell activation. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-64480312-G-A is Benign according to our data. Variant chr17-64480312-G-A is described in ClinVar as Benign. ClinVar VariationId is 138784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007215.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG2	NM_007215.4	MANE Select	c.1269C>T	p.Ser423Ser	synonymous	Exon 7 of 8	NP_009146.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG2	ENST00000539111.7	TSL:1 MANE Select	c.1269C>T	p.Ser423Ser	synonymous	Exon 7 of 8	ENSP00000442563.2
	POLG2	ENST00000577506.5	TSL:5	n.449C>T		non_coding_transcript_exon	Exon 4 of 4
	POLG2	ENST00000582501.5	TSL:5	n.877C>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.0823 AC: 12509 AN: 151986 Hom.: 637 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.0568

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.0439

Gnomad FIN AF: 0.0583

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0714

GnomAD2 exomes AF: 0.0729 AC: 18300 AN: 250934 AF XY: 0.0681

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0519

Gnomad EAS exome AF: 0.0305

Gnomad FIN exome AF: 0.0620

Gnomad NFE exome AF: 0.0623

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0596 AC: 84616 AN: 1420340 Hom.: 3018 Cov.: 23 AF XY: 0.0589 AC XY: 41734 AN XY: 708876

African (AFR) AF: 0.109 AC: 3554 AN: 32590

American (AMR) AF: 0.154 AC: 6861 AN: 44446

Ashkenazi Jewish (ASJ) AF: 0.0527 AC: 1358 AN: 25754

East Asian (EAS) AF: 0.0342 AC: 1342 AN: 39202

South Asian (SAS) AF: 0.0417 AC: 3557 AN: 85232

European-Finnish (FIN) AF: 0.0624 AC: 3290 AN: 52742

Middle Eastern (MID) AF: 0.0474 AC: 269 AN: 5670

European-Non Finnish (NFE) AF: 0.0567 AC: 60995 AN: 1075878

Other (OTH) AF: 0.0576 AC: 3390 AN: 58826

GnomAD4 genome AF: 0.0823 AC: 12516 AN: 152104 Hom.: 638 Cov.: 32 AF XY: 0.0844 AC XY: 6276 AN XY: 74344

African (AFR) AF: 0.109 AC: 4513 AN: 41490

American (AMR) AF: 0.153 AC: 2345 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 197 AN: 3470

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5178

South Asian (SAS) AF: 0.0440 AC: 212 AN: 4820

European-Finnish (FIN) AF: 0.0583 AC: 615 AN: 10544

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0628 AC: 4269 AN: 68008

Other (OTH) AF: 0.0706 AC: 149 AN: 2110

Alfa AF: 0.0677 Hom.: 197

Bravo AF: 0.0871

Asia WGS AF: 0.0450 AC: 158 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs61733782; hg19: chr17-62476429; COSMIC: COSV73376903; COSMIC: COSV73376903;