11-61398269-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBA1

The ENST00000334888.10(TMEM216):c.440G>C(p.Arg147Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.828 in 1,607,904 control chromosomes in the GnomAD database, including 560,838 homozygotes. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.72 ( 43218 hom., cov: 31)

Exomes 𝑓: 0.84 ( 517620 hom. )

Consequence

TMEM216
ENST00000334888.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.817

Publications

42 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: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 11-61398269-G-C is Benign according to our data. Variant chr11-61398269-G-C is described in ClinVar as Benign. ClinVar VariationId is 126297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3 link	c.432-1G>C		splice_acceptor_variant, intron_variant	Intron 4 of 4	ENST00000515837.7	NP_001167461.1	Q9P0N5-1
TMEM216	NM_001173991.3 link	c.440G>C	p.Arg147Thr	missense_variant	Exon 5 of 5		NP_001167462.1	Q9P0N5-3
TMEM216	NM_016499.6 link	c.257G>C	p.Arg86Thr	missense_variant	Exon 5 of 5		NP_057583.2	Q9P0N5-2
TMEM216	NM_001330285.2 link	c.249-1G>C		splice_acceptor_variant, intron_variant	Intron 4 of 4		NP_001317214.1	Q9P0N5J3QT25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000334888.10 link	c.440G>C	p.Arg147Thr	missense_variant	Exon 5 of 5	2		ENSP00000334844.5		Q9P0N5-3
TMEM216	ENST00000515837.7 link	c.432-1G>C		splice_acceptor_variant, intron_variant	Intron 4 of 4	2	NM_001173990.3	ENSP00000440638.1		Q9P0N5-1

Frequencies

GnomAD3 genomes

AF:

0.722

AC:

109477

AN:

151722

Hom.:

43221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.367

Gnomad AMI

AF:

0.913

Gnomad AMR

AF:

0.825

Gnomad ASJ

AF:

0.891

Gnomad EAS

AF:

0.971

Gnomad SAS

AF:

0.820

Gnomad FIN

AF:

0.883

Gnomad MID

AF:

0.856

Gnomad NFE

AF:

0.850

Gnomad OTH

AF:

0.771

GnomAD2 exomes

AF:

0.831

AC:

203288

AN:

244770

AF XY:

0.837

show subpopulations

Gnomad AFR exome

AF:

0.350

Gnomad AMR exome

AF:

0.862

Gnomad ASJ exome

AF:

0.891

Gnomad EAS exome

AF:

0.962

Gnomad FIN exome

AF:

0.877

Gnomad NFE exome

AF:

0.849

Gnomad OTH exome

AF:

0.853

GnomAD4 exome

AF:

0.839

AC:

1221387

AN:

1456064

Hom.:

517620

Cov.:

AF XY:

0.841

AC XY:

608994

AN XY:

724150

show subpopulations

African (AFR)

AF:

0.345

AC:

11527

AN:

33402

American (AMR)

AF:

0.861

AC:

38067

AN:

44192

Ashkenazi Jewish (ASJ)

AF:

0.887

AC:

23064

AN:

25998

East Asian (EAS)

AF:

0.971

AC:

38529

AN:

39662

South Asian (SAS)

AF:

0.838

AC:

71860

AN:

85732

European-Finnish (FIN)

AF:

0.880

AC:

46752

AN:

53152

Middle Eastern (MID)

AF:

0.856

AC:

4924

AN:

5752

European-Non Finnish (NFE)

AF:

0.845

AC:

936673

AN:

1107994

Other (OTH)

AF:

0.831

AC:

49991

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

9529

19058

28586

38115

47644

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20942

41884

62826

83768

104710

<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:

0.721

AC:

109486

AN:

151840

Hom.:

43218

Cov.:

AF XY:

0.728

AC XY:

54023

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.367

AC:

15196

AN:

41428

American (AMR)

AF:

0.825

AC:

12609

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.891

AC:

3091

AN:

3468

East Asian (EAS)

AF:

0.971

AC:

5019

AN:

5170

South Asian (SAS)

AF:

0.821

AC:

3937

AN:

4798

European-Finnish (FIN)

AF:

0.883

AC:

9305

AN:

10540

Middle Eastern (MID)

AF:

0.852

AC:

247

AN:

290

European-Non Finnish (NFE)

AF:

0.850

AC:

57636

AN:

67846

Other (OTH)

AF:

0.765

AC:

1615

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1190

2381

3571

4762

5952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.822

Hom.:

11912

Bravo

AF:

0.702

ESP6500AA

AF:

0.392

AC:

1528

ESP6500EA

AF:

0.850

AC:

7072

ExAC

AF:

0.813

AC:

98226

Asia WGS

AF:

0.824

AC:

2866

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Apr 25, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TMEM216 c.432-1G>C is located in the last canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.83 in 244770 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 216 fold of the estimated maximal expected allele frequency for a pathogenic variant in TMEM216 causing Joubert Syndrome 2 phenotype (0.0039). To our knowledge, no occurrence of c.432-1G>C in individuals affected with Joubert Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 126297). Based on the evidence outlined above, the variant was classified as benign. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 04, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Meckel syndrome, type 2

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 2

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joubert syndrome

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Benign

0.69

PhyloP100

0.82

ClinPred

0.018

GERP RS

4.1

Mutation Taster

=66/34

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 15

DS_AL_spliceai

0.79

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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