NM_003730.6:c.648G>A

Variant names:

• chr6-166929711-C-T
• rs35517174
• NM_003730.6:c.648G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003730.6(RNASET2):​c.648G>A​(p.Pro216Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,046 control chromosomes in the GnomAD database, including 1,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (360 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (673 hom.)
• Consequence: RNASET2 NM_003730.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.91

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]

ENSG00000249141 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-166929711-C-T is Benign according to our data. Variant chr6-166929711-C-T is described in ClinVar as [Benign]. Clinvar id is 356029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-166929711-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.91 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNASET2	NM_003730.6	c.648G>A	p.Pro216Pro	synonymous_variant	Exon 9 of 9	ENST00000508775.6	NP_003721.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNASET2	ENST00000508775.6	c.648G>A	p.Pro216Pro	synonymous_variant	Exon 9 of 9	1	NM_003730.6	ENSP00000426455.2
ENSG00000249141	ENST00000507747.1	c.432+4380G>A		intron_variant	Intron 7 of 7	5		ENSP00000426906.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6296 AN: 152068 Hom.: 358 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0780

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0288

GnomAD3 exomes AF: 0.0189 AC: 4762 AN: 251412 Hom.: 222 AF XY: 0.0167 AC XY: 2272 AN XY: 135900

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.00945

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0688

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00109

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.00884 AC: 12921 AN: 1461860 Hom.: 673 Cov.: 31 AF XY: 0.00886 AC XY: 6444 AN XY: 727236

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00356

Gnomad4 EAS exome AF: 0.0992

Gnomad4 SAS exome AF: 0.0223

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000738

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0415 AC: 6313 AN: 152186 Hom.: 360 Cov.: 33 AF XY: 0.0409 AC XY: 3042 AN XY: 74398

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.0781

Gnomad4 SAS AF: 0.0233

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.00790 Hom.: 67

Bravo AF: 0.0468

Asia WGS AF: 0.0670 AC: 233 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic leukoencephalopathy without megalencephaly Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.011
DANN	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35517174; hg19: chr6-167343199; COSMIC: COSV50351288; COSMIC: COSV50351288;