Genetic Variant TNRC6B:p.Gln18Lys (chr22-40156121-C-A) – 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 ENST00000402203.5(TNRC6B):c.52C>A(p.Gln18Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TNRC6B
ENST00000402203.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.81

Publications

0 publications found

Variant links:

Genes affected

TNRC6B (HGNC:29190): (trinucleotide repeat containing adaptor 6B) Enables RNA binding activity. Involved in regulation of gene expression. Predicted to be located in cytosol. Predicted to be active in P-body and nucleoplasm. Implicated in subserous uterine fibroid and uterine fibroid. [provided by Alliance of Genome Resources, Apr 2022]

TNRC6B Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
global developmental delay with speech and behavioral abnormalities
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TNRC6B links:

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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=0.1690019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001024843.2 link	c.52C>A	p.Gln18Lys	missense_variant	Exon 4 of 24		NP_001020014.1	Q9UPQ9-2A0A024R1N5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000402203.5 link	c.52C>A	p.Gln18Lys	missense_variant	Exon 4 of 24	1		ENSP00000384795.1		Q9UPQ9-2
TNRC6B	ENST00000301923.13 link	c.52C>A	p.Gln18Lys	missense_variant	Exon 4 of 24	5		ENSP00000306759.9		Q9UPQ9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1426950

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706022

African (AFR)

AF:

0.00

AC:

AN:

32838

American (AMR)

AF:

0.00

AC:

AN:

39114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25428

East Asian (EAS)

AF:

0.00

AC:

AN:

38298

South Asian (SAS)

AF:

0.00

AC:

AN:

80924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1093964

Other (OTH)

AF:

0.00

AC:

AN:

59256

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 19, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Reported using an alternate transcript of the gene -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.093

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.74

T;T;.

M_CAP

Benign

0.0098

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

4.8

PROVEAN

Uncertain

-3.4

D;N;N

REVEL

Benign

0.066

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.37

T;T;T

Polyphen

0.012

.;B;B

Vest4

0.26, 0.28

MutPred

0.27

Gain of ubiquitination at Q18 (P = 0.0022);Gain of ubiquitination at Q18 (P = 0.0022);Gain of ubiquitination at Q18 (P = 0.0022);

MVP

0.29

ClinPred

0.78

GERP RS

5.7

Mutation Taster

=72/28

polymorphism

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over