Genetic Variant RNASET2:c.446+279G>C (chr6-166938616-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003730.6(RNASET2):c.446+279G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 535,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

RNASET2
NM_003730.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0370

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

cystic leukoencephalopathy without megalencephaly
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia, Orphanet

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17613667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASET2	NM_003730.6 link	c.446+279G>C		intron_variant	Intron 6 of 8	ENST00000508775.6	NP_003721.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASET2	ENST00000508775.6 link	c.446+279G>C		intron_variant	Intron 6 of 8	1	NM_003730.6	ENSP00000426455.2
ENSG00000249141	ENST00000507747.1 link	c.386+279G>C		intron_variant	Intron 6 of 7	5		ENSP00000426906.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000413

AC:

AN:

242290

AF XY:

0.00000752

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:

0.00000930

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000187

AC:

AN:

535798

Hom.:

Cov.:

AF XY:

0.00000339

AC XY:

AN XY:

294980

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

15618

American (AMR)

AF:

0.00

AC:

AN:

40814

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18064

East Asian (EAS)

AF:

0.00

AC:

AN:

27044

South Asian (SAS)

AF:

0.00

AC:

AN:

68140

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3696

European-Non Finnish (NFE)

AF:

0.00000342

AC:

AN:

292408

Other (OTH)

AF:

0.00

AC:

AN:

27488

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000843

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.91

CADD

Benign

1.1

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.0094

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.28

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

PhyloP100

0.037

Sift4G

Benign

0.12

Vest4

0.33

MVP

0.19

ClinPred

0.065

GERP RS

0.20

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over