6-166929716-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003730.6(RNASET2):c.643G>A(p.Glu215Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,614,092 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (26 hom.)
• Consequence: RNASET2 NM_003730.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.589

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=0.005907774).
• BP6: Variant 6-166929716-C-T is Benign according to our data. Variant chr6-166929716-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 356030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-166929716-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00437 (666/152238) while in subpopulation AMR AF= 0.0072 (110/15284). AF 95% confidence interval is 0.00611. There are 1 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNASET2	NM_003730.6	c.643G>A	p.Glu215Lys	missense_variant	9/9	ENST00000508775.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNASET2	ENST00000508775.6	c.643G>A	p.Glu215Lys	missense_variant	9/9	1	NM_003730.6	P1

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152120 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00721

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00598

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00437 AC: 1098 AN: 251406 Hom.: 5 AF XY: 0.00411 AC XY: 559 AN XY: 135896

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00622

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.00528

Gnomad OTH exome AF: 0.00815

GnomAD4 exome AF: 0.00539 AC: 7881 AN: 1461854 Hom.: 26 Cov.: 31 AF XY: 0.00519 AC XY: 3774 AN XY: 727230

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00662

Gnomad4 ASJ exome AF: 0.0137

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00264

Gnomad4 NFE exome AF: 0.00603

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00437 AC: 666 AN: 152238 Hom.: 1 Cov.: 33 AF XY: 0.00426 AC XY: 317 AN XY: 74438

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00720

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00598

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00536 Hom.: 5

Bravo AF: 0.00458

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00400 AC: 485

EpiCase AF: 0.00616

EpiControl AF: 0.00486

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RNASET2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -

Cystic leukoencephalopathy without megalencephaly Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

RNASET2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.82	T;.;T;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0059	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N;N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.19	T;T;.;T;T
Sift4G	Uncertain	0.027	D;T;D;T;.
Polyphen		0.57	.;P;.;P;.
Vest4		0.17
MVP		0.78
MPC		0.41
ClinPred		0.024	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.098
gMVP		0.46

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: rs41269593; hg19: chr6-167343204; COSMIC: COSV50352027; COSMIC: COSV50352027;