11-61393965-G-A

Position:

chr11-61393965-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_001173990.3(TMEM216):c.218G>A(p.Arg73His) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,754 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TMEM216
NM_001173990.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.70

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001173990.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-61393965-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.897

PP5

Variant 11-61393965-G-A is Pathogenic according to our data. Variant chr11-61393965-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61393965-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TMEM216	NM_001173990.3 linkuse as main transcript	c.218G>A	p.Arg73His	missense_variant	3/5	ENST00000515837.7
TMEM216	NM_001173991.3 linkuse as main transcript	c.218G>A	p.Arg73His	missense_variant	3/5
TMEM216	NM_016499.6 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	3/5
TMEM216	NM_001330285.2 linkuse as main transcript	c.35G>A	p.Arg12His	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7 linkuse as main transcript	c.218G>A	p.Arg73His	missense_variant	3/5	2	NM_001173990.3	P4	Q9P0N5-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249228

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Meckel syndrome, type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -

Joubert syndrome 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 07, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2010	- -

Familial aplasia of the vermis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 73 of the TMEM216 protein (p.Arg73His). This variant is present in population databases (rs201108965, gnomAD 0.01%). This missense change has been observed in individual(s) with Joubert syndrome-related disorders (PMID: 20512146). ClinVar contains an entry for this variant (Variation ID: 198). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TMEM216 function (PMID: 20512146). This variant disrupts the p.Arg73 amino acid residue in TMEM216. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20036350, 20512146, 26092869, 26673778). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.

Eigen

Benign

0.0016

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.3

D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.053

T;T;T

Vest4

0.97

MVP

0.75

MPC

0.48

ClinPred

0.97

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.55

gMVP

0.89

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over