chr6-166929648-A-AC

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_003730.6(RNASET2):c.710dupG(p.Leu238SerfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

RNASET2
NM_003730.6 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.181

Variant links:

Genes affected

RNASET2 (HGNC:21686): (ribonuclease T2) This ribonuclease gene is a novel member of the Rh/T2/S-glycoprotein class of extracellular ribonucleases. It is a single copy gene that maps to 6q27, a region associated with human malignancies and chromosomal rearrangement. [provided by RefSeq, Jul 2008]

RNASET2 links:

ENSG00000249141 (HGNC:):

ENSG00000249141 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0791 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-166929648-A-AC is Pathogenic according to our data. Variant chr6-166929648-A-AC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436545.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASET2	NM_003730.6 link	c.710dupG	p.Leu238SerfsTer5	frameshift_variant	Exon 9 of 9	ENST00000508775.6	NP_003721.2	O00584-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASET2	ENST00000508775.6 link	c.710dupG	p.Leu238SerfsTer5	frameshift_variant	Exon 9 of 9	1	NM_003730.6	ENSP00000426455.2		O00584-1
ENSG00000249141	ENST00000507747.1 link	c.432+4442dupG		intron_variant	Intron 7 of 7	5		ENSP00000426906.1		H0YAE9

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151166

Hom.:

Cov.:

show subpopulations

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:

0.0000738

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251430

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000615

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.0000562

AC:

AN:

53414

Gnomad4 NFE exome

AF:

0.0000504

AC:

AN:

1112012

Gnomad4 Remaining exome

AF:

0.0000331

AC:

AN:

60396

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000331

AC:

AN:

151166

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73762

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000738

AC:

0.0000738225

AN:

0.0000738225

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000680

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic leukoencephalopathy without megalencephaly

Pathogenic:1

Nov 17, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 30, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RNASET2 c.710dupG (p.Leu238SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein. No downstream pathogenic variants have been reported. The variant allele was found at a frequency of 2.8e-05 in 251430 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.710dupG has been reported in the literature in one individual affected with Cystic leukoencephalopathy without megalencephaly (Kuster_2017, Rice_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28924877, 27943079). ClinVar contains an entry for this variant (Variation ID: 436545). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=51/149

disease causing (ClinVar)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over