chr6-166929662-C-T

Variant names:

• chr6-166929662-C-T
• rs149922066
• NM_003730.6:c.697G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003730.6(RNASET2):​c.697G>A​(p.Ala233Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000978 in 1,614,092 control chromosomes in the GnomAD database, including 14 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. A233A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (5 hom.)
• Consequence: RNASET2 NM_003730.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.08
• Publications: 3 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet, Illumina

ENSG00000249141 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040089786).
• BP6: Variant 6-166929662-C-T is Benign according to our data. Variant chr6-166929662-C-T is described in ClinVar as Benign. ClinVar VariationId is 776184.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00558 (850/152244) while in subpopulation AFR AF = 0.0195 (812/41544). AF 95% confidence interval is 0.0184. There are 9 homozygotes in GnomAd4. There are 403 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003730.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASET2	NM_003730.6	MANE Select	c.697G>A	p.Ala233Thr	missense	Exon 9 of 9	NP_003721.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNASET2	ENST00000508775.6	TSL:1 MANE Select	c.697G>A	p.Ala233Thr	missense	Exon 9 of 9	ENSP00000426455.2	O00584-1
	ENSG00000249141	ENST00000507747.1	TSL:5	c.432+4429G>A		intron	N/A	ENSP00000426906.1	H0YAE9
	RNASET2	ENST00000870284.1		c.835G>A	p.Ala279Thr	missense	Exon 10 of 10	ENSP00000540343.1

Frequencies

GnomAD3 genomes AF: 0.00556 AC: 846 AN: 152126 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00140 AC: 352 AN: 251396 AF XY: 0.000979

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000498 AC: 728 AN: 1461848 Hom.: 5 Cov.: 31 AF XY: 0.000396 AC XY: 288 AN XY: 727220

African (AFR) AF: 0.0177 AC: 594 AN: 33480

American (AMR) AF: 0.000604 AC: 27 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1111990

Other (OTH) AF: 0.00104 AC: 63 AN: 60396

GnomAD4 genome AF: 0.00558 AC: 850 AN: 152244 Hom.: 9 Cov.: 33 AF XY: 0.00541 AC XY: 403 AN XY: 74436

African (AFR) AF: 0.0195 AC: 812 AN: 41544

American (AMR) AF: 0.00176 AC: 27 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00313 Hom.: 4

Bravo AF: 0.00641

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00187 AC: 227

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	RNASET2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.14
DANN	Benign	0.50
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.48	N
PhyloP100		-1.1
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.10
Sift	Benign	0.81	T
Sift4G	Benign	0.70	T
Polyphen		0.026	B
Vest4		0.017
MVP		0.27
MPC		0.22
ClinPred		0.0036	T
GERP RS		-6.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.33
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs149922066; hg19: chr6-167343150; COSMIC: COSV107213285; COSMIC: COSV107213285;