rs147953784

Positions:

• chr11-61393214-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_001173990.3(TMEM216):​c.35-17C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,530,872 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (65 hom.)
• Consequence: TMEM216 NM_001173990.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.113

Genes affected

TMEM216 (HGNC:25018): (transmembrane protein 216) This locus encodes a transmembrane domain-containing protein. Mutations at this locus have been associated with Meckel-Gruber Syndrome Type 2, and Joubert Syndrome 2, also known as Cerebello-oculorenal Syndrome 2. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-61393214-C-T is Benign according to our data. Variant chr11-61393214-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61393214-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00513 (782/152312) while in subpopulation SAS AF= 0.024 (116/4830). AF 95% confidence interval is 0.0205. There are 6 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM216	NM_001173990.3	c.35-17C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000515837.7
TMEM216	NM_001173991.3	c.35-17C>T		splice_polypyrimidine_tract_variant, intron_variant
TMEM216	NM_001330285.2	c.-149-17C>T		splice_polypyrimidine_tract_variant, intron_variant
TMEM216	NM_016499.6	c.-149-17C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.35-17C>T		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 783 AN: 152194 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0242

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00663

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00785 AC: 1067 AN: 135982 Hom.: 11 AF XY: 0.00933 AC XY: 689 AN XY: 73846

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.00477

Gnomad ASJ exome AF: 0.00146

Gnomad EAS exome AF: 0.000287

Gnomad SAS exome AF: 0.0225

Gnomad FIN exome AF: 0.00507

Gnomad NFE exome AF: 0.00686

Gnomad OTH exome AF: 0.00703

GnomAD4 exome AF: 0.00577 AC: 7956 AN: 1378560 Hom.: 65 Cov.: 28 AF XY: 0.00647 AC XY: 4400 AN XY: 680562

Gnomad4 AFR exome AF: 0.000762

Gnomad4 AMR exome AF: 0.00455

Gnomad4 ASJ exome AF: 0.00243

Gnomad4 EAS exome AF: 0.000224

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.00513 AC: 782 AN: 152312 Hom.: 6 Cov.: 32 AF XY: 0.00563 AC XY: 419 AN XY: 74480

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00663

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00692 Hom.: 1

Bravo AF: 0.00474

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 28, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Joubert syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 19, 2019	- -

Meckel syndrome, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.5
DANN	Benign	0.55

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: rs147953784; hg19: chr11-61160686;