11-61397797-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001173990.3(TMEM216):c.253C>T(p.Arg85*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R85R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

TMEM216
NM_001173990.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.26

Publications

9 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Joubert syndrome 2
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Joubert syndrome with oculorenal defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
orofaciodigital syndrome type 6
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TMEM216 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-61397797-C-T is Pathogenic according to our data. Variant chr11-61397797-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 56384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3 link	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	ENST00000515837.7	NP_001167461.1	Q9P0N5-1
TMEM216	NM_001173991.3 link	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5		NP_001167462.1	Q9P0N5-3
TMEM216	NM_016499.6 link	c.70C>T	p.Arg24*	stop_gained	Exon 4 of 5		NP_057583.2	Q9P0N5-2
TMEM216	NM_001330285.2 link	c.70C>T	p.Arg24*	stop_gained	Exon 4 of 5		NP_001317214.1	Q9P0N5J3QT25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7 link	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	2	NM_001173990.3	ENSP00000440638.1		Q9P0N5-1
TMEM216	ENST00000334888.10 link	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	2		ENSP00000334844.5		Q9P0N5-3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000804

AC:

AN:

248910

AF XY:

0.0000593

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461166

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.000134

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5346

European-Non Finnish (NFE)

AF:

0.000181

AC:

201

AN:

1111846

Other (OTH)

AF:

0.000265

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41452

American (AMR)

AF:

0.000131

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68042

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Jun 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2, PS3, PVS1 -

Jul 24, 2017

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in homozygous state in two siblings with Meckel syndrome in published literature (Valente et al., 2010; Szymanska et al., 2012) and in a fetus with encephalocele, kidney anomaly, eye abnormality, microcephaly, club foot, and short limbs previously tested at GeneDx, and not observed in homozygous state in controls; Observed in the heterozygous state with another variant in the TMEM216 gene in a patient with Joubert syndrome in published literature; however, it is unknown whether the two variants were present in cis or trans (Bachmann-Gagescu et al., 2015; Summers et al., 2017); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20512146, 21068128, 23351400, 26092869, 28497568, 31589614) -

Joubert syndrome 2

Pathogenic:3

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 21, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 05, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TMEM216 c.253C>T (p.Arg85X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.7e-05 in 276782 control chromosomes. This frequency is not higher than expected for a pathogenic variant in TMEM216 causing Joubert Syndrome 2 (8.7e-05 vs 0.0039), allowing no conclusion about variant significance. c.253C>T has been reported in the literature in individuals affected with Meckel syndrome 2 or Joubert Syndrome 2 (Valente 2010, Summers 2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating the loss of protein expression and a failure in ciliogenesis and centrosome docking (Valente 2010). The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Joubert syndrome 2;C1864148:Meckel syndrome, type 2

Pathogenic:2

Feb 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 02, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

TMEM216-related disorder

Pathogenic:2

Jun 27, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TMEM216 c.253C>T variant is predicted to result in premature protein termination (p.Arg85*). This variant has been reported in the homozygous state in two fetuses with Meckel-Gruber syndrome from one family (Valente et al 2010. PubMed ID: 20512146). This variant has also been reported in the homozygous or heterozygous states in individuals with Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26092869. Table S5; Summers et al. 2017. PubMed ID: 28497568. Table S2; Szymanska et al. 2012. PubMed ID: 23351400). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-61165269-C-T). Nonsense variants in TMEM216 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Oct 11, 2018

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TMEM216 c.253C>T (p.Arg85Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. The p.Arg85Ter variant has been reported in at least two studies in which it is found in at least three individuals, including two siblings with Meckel syndrome who carried the variant in a homozygous state and one individual with Joubert syndrome who carried the variant in a compound heterozygous state (Valente et al. 2010; Bachmann-Gogescu et al. 2015). The p.Arg85Ter variant was absent from 500 controls, but is reported at a frequency of 0.00003 in the total population from the Exome Aggregation Consortium. In fibroblasts that were homozygous for the p.Arg85Ter variant, there was failure of ciliogenesis after 48h compared to controls (Valente et al. 2010). Further, this variant protein was not observed at the base of cilia in kidney cells, whereas wild type protein was observed at this location. Based on the evidence and the potential impact of stop-gained variants, the p.Arg85Ter variant is classified as pathogenic for TMEM216-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Meckel syndrome, type 2

Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Joubert syndrome

Pathogenic:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg85*) in the TMEM216 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM216 are known to be pathogenic (PMID: 20512146). This variant is present in population databases (rs11230683, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Meckel syndrome or Joubert syndrome (PMID: 20512146, 23351400, 26092869, 28497568). ClinVar contains an entry for this variant (Variation ID: 56384). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.42

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.84

PhyloP100

1.3

Vest4

0.55

GERP RS

2.7

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over