rs3741265

Positions:

• chr11-61397808-G-A
• chr11-61397808-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001173990.3(TMEM216):​c.264G>A​(p.Pro88Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.859 in 1,613,466 control chromosomes in the GnomAD database, including 595,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54411 hom., cov: 32)
  • Exomes 𝑓: 0.86 (541421 hom.)
• Consequence: TMEM216 NM_001173990.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.97

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]

TMEM216 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-61397808-G-A is Benign according to our data. Variant chr11-61397808-G-A is described in ClinVar as [Benign]. Clinvar id is 126296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61397808-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.264G>A	p.Pro88Pro	synonymous_variant	4/5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.264G>A	p.Pro88Pro	synonymous_variant	4/5		NP_001167462.1
TMEM216	NM_016499.6	c.81G>A	p.Pro27Pro	synonymous_variant	4/5		NP_057583.2
TMEM216	NM_001330285.2	c.81G>A	p.Pro27Pro	synonymous_variant	4/5		NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.264G>A	p.Pro88Pro	synonymous_variant	4/5	2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.264G>A	p.Pro88Pro	synonymous_variant	4/5	2		ENSP00000334844.5

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128384 AN: 152080 Hom.: 54388 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.975

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.864

GnomAD3 exomes AF: 0.871 AC: 216972 AN: 249036 Hom.: 94825 AF XY: 0.872 AC XY: 117784 AN XY: 135058

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 0.967

Gnomad SAS exome AF: 0.866

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.863

Gnomad OTH exome AF: 0.878

GnomAD4 exome AF: 0.860 AC: 1256957 AN: 1461268 Hom.: 541421 Cov.: 56 AF XY: 0.861 AC XY: 626049 AN XY: 726934

Gnomad4 AFR exome AF: 0.760

Gnomad4 AMR exome AF: 0.887

Gnomad4 ASJ exome AF: 0.893

Gnomad4 EAS exome AF: 0.973

Gnomad4 SAS exome AF: 0.869

Gnomad4 FIN exome AF: 0.884

Gnomad4 NFE exome AF: 0.855

Gnomad4 OTH exome AF: 0.869

GnomAD4 genome AF: 0.844 AC: 128458 AN: 152198 Hom.: 54411 Cov.: 32 AF XY: 0.848 AC XY: 63090 AN XY: 74404

Gnomad4 AFR AF: 0.769

Gnomad4 AMR AF: 0.874

Gnomad4 ASJ AF: 0.897

Gnomad4 EAS AF: 0.975

Gnomad4 SAS AF: 0.857

Gnomad4 FIN AF: 0.887

Gnomad4 NFE AF: 0.861

Gnomad4 OTH AF: 0.857

Alfa AF: 0.854 Hom.: 70239

Bravo AF: 0.838

Asia WGS AF: 0.876 AC: 3046 AN: 3478

EpiCase AF: 0.866

EpiControl AF: 0.863

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 15, 2011	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2016	Variant summary: The TMEM216 c.264G>A (p.Pro88Pro) variant affects a non-conserved nucleotide, resulting in a synonymous mutation. Mutation taster predicts the variant to be a polymorphism along with 5/5 in silico tools via Alamut predicting the variant not to affect splicing. This variant is found in 104584/120784 control chromosomes (45445 homozygotes) at a frequency of 0.8658763, suggesting this variant to be the ancestral allele; therefore it is classified as Benign. -

Joubert syndrome 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Meckel syndrome, type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.46
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3741265; hg19: chr11-61165280;