22-40312675-T-C

Variant names:

• chr22-40312675-T-C
• rs2072858
• NM_001162501.2:c.4582+24T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001162501.2(TNRC6B):​c.4582+24T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,601,200 control chromosomes in the GnomAD database, including 105,185 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8325 hom., cov: 32)
  • Exomes 𝑓: 0.36 (96860 hom.)
• Consequence: TNRC6B NM_001162501.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.460
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNRC6B	NM_001162501.2	c.4582+24T>C		intron_variant	Intron 18 of 22	ENST00000454349.7	NP_001155973.1
TNRC6B	NM_015088.3	c.4252+24T>C		intron_variant	Intron 16 of 20		NP_055903.2
TNRC6B	NM_001024843.2	c.2170+24T>C		intron_variant	Intron 19 of 23		NP_001020014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNRC6B	ENST00000454349.7	c.4582+24T>C		intron_variant	Intron 18 of 22	2	NM_001162501.2	ENSP00000401946.2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47688 AN: 151926 Hom.: 8316 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.345

Gnomad OTH AF: 0.304

GnomAD2 exomes AF: 0.389 AC: 93062 AN: 239282 AF XY: 0.387

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.586

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.417

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.346

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.360 AC: 521409 AN: 1449156 Hom.: 96860 Cov.: 34 AF XY: 0.362 AC XY: 260788 AN XY: 719842

African (AFR) AF: 0.160 AC: 5292 AN: 33068

American (AMR) AF: 0.563 AC: 24017 AN: 42640

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 7843 AN: 25528

East Asian (EAS) AF: 0.447 AC: 17691 AN: 39568

South Asian (SAS) AF: 0.453 AC: 38009 AN: 83838

European-Finnish (FIN) AF: 0.390 AC: 20700 AN: 53126

Middle Eastern (MID) AF: 0.275 AC: 1570 AN: 5716

European-Non Finnish (NFE) AF: 0.349 AC: 386026 AN: 1105788

Other (OTH) AF: 0.338 AC: 20261 AN: 59884

GnomAD4 genome AF: 0.314 AC: 47718 AN: 152044 Hom.: 8325 Cov.: 32 AF XY: 0.323 AC XY: 23968 AN XY: 74318

African (AFR) AF: 0.171 AC: 7095 AN: 41514

American (AMR) AF: 0.424 AC: 6474 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1038 AN: 3470

East Asian (EAS) AF: 0.422 AC: 2184 AN: 5174

South Asian (SAS) AF: 0.469 AC: 2254 AN: 4810

European-Finnish (FIN) AF: 0.395 AC: 4166 AN: 10552

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.345 AC: 23424 AN: 67932

Other (OTH) AF: 0.306 AC: 645 AN: 2108

Alfa AF: 0.346 Hom.: 6035

Bravo AF: 0.311

Asia WGS AF: 0.477 AC: 1658 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.37
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs2072858; hg19: chr22-40708679; COSMIC: COSV57302867;