6-166929653-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003730.6(RNASET2):c.706C>T(p.Arg236Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0717 in 1,613,952 control chromosomes in the GnomAD database, including 4,376 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R236Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.079 (518 hom., cov: 33)
  • Exomes 𝑓: 0.071 (3858 hom.)
• Consequence: RNASET2 NM_003730.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.601

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001725316).
• BP6: Variant 6-166929653-G-A is Benign according to our data. Variant chr6-166929653-G-A is described in ClinVar as [Benign]. Clinvar id is 356027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-166929653-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASET2	NM_003730.6	c.706C>T	p.Arg236Trp	missense_variant	9/9	ENST00000508775.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASET2	ENST00000508775.6	c.706C>T	p.Arg236Trp	missense_variant	9/9	1	NM_003730.6	P1

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12046 AN: 151986 Hom.: 517 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0418

Gnomad AMR AF: 0.0663

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0597

Gnomad SAS AF: 0.0558

Gnomad FIN AF: 0.0555

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0694

Gnomad OTH AF: 0.0772

GnomAD3 exomes AF: 0.0689 AC: 17325 AN: 251354 Hom.: 664 AF XY: 0.0693 AC XY: 9415 AN XY: 135882

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0478

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.0633

Gnomad SAS exome AF: 0.0577

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0706

Gnomad OTH exome AF: 0.0738

GnomAD4 exome AF: 0.0709 AC: 103612 AN: 1461848 Hom.: 3858 Cov.: 31 AF XY: 0.0709 AC XY: 51578 AN XY: 727230

Gnomad4 AFR exome AF: 0.107

Gnomad4 AMR exome AF: 0.0505

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.0468

Gnomad4 SAS exome AF: 0.0601

Gnomad4 FIN exome AF: 0.0593

Gnomad4 NFE exome AF: 0.0712

Gnomad4 OTH exome AF: 0.0753

GnomAD4 genome AF: 0.0793 AC: 12061 AN: 152104 Hom.: 518 Cov.: 33 AF XY: 0.0777 AC XY: 5776 AN XY: 74372

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0662

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.0596

Gnomad4 SAS AF: 0.0559

Gnomad4 FIN AF: 0.0555

Gnomad4 NFE AF: 0.0694

Gnomad4 OTH AF: 0.0769

Alfa AF: 0.0749 Hom.: 415

Bravo AF: 0.0815

TwinsUK AF: 0.0728 AC: 270

ALSPAC AF: 0.0747 AC: 288

ESP6500AA AF: 0.109 AC: 482

ESP6500EA AF: 0.0767 AC: 660

ExAC AF: 0.0695 AC: 8433

Asia WGS AF: 0.0680 AC: 238 AN: 3478

EpiCase AF: 0.0779

EpiControl AF: 0.0730

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic leukoencephalopathy without megalencephaly Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.97
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.70	T;.;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.4	N;N;.;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.018	D;D;.;D;D
Sift4G	Uncertain	0.018	D;D;D;D;.
Polyphen		0.99	.;D;.;D;.
Vest4		0.12
MPC		0.56
ClinPred		0.017	T
GERP RS		0.021
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.44

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

Other links and lift over

dbSNP: rs11159; hg19: chr6-167343141; COSMIC: COSV50351546; COSMIC: COSV50351546;