11-61397797-C-T

Variant names:

• chr11-61397797-C-T
• rs11230683
• NM_001173990.3:c.253C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000920296: 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)." and additional evidence is available in ClinVar. 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 1.26
• Publications: 9 publications found

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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000920296: 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).; SCV000915534: "In fibroblasts that were homozygous for the p.Arg85Ter variant, there was failure of ciliogenesis after 48h compared to controls (Valente et al. 2010)."
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173990.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	NM_001173990.3	MANE Select	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.70C>T	p.Arg24*	stop_gained	Exon 4 of 5	NP_057583.2	Q9P0N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.253C>T	p.Arg85*	stop_gained	Exon 4 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.70C>T	p.Arg24*	stop_gained	Exon 4 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152206 Hom.: 0 Cov.: 31

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: 20 AN: 248910 AF XY: 0.0000593

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.: 0 Cov.: 29 AF XY: 0.000140 AC XY: 102 AN XY: 726880

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5346

European-Non Finnish (NFE) AF: 0.000181 AC: 201 AN: 1111846

Other (OTH) AF: 0.000265 AC: 16 AN: 60328

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152206 Hom.: 0 Cov.: 31 AF XY: 0.0000941 AC XY: 7 AN XY: 74352

African (AFR) AF: 0.0000965 AC: 4 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000243 AC: 1

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Joubert syndrome 2 (3)
3	-	-	not provided (3)
2	-	-	Joubert syndrome 2;C1864148:Meckel syndrome, type 2 (2)
2	-	-	TMEM216-related disorder (2)
1	-	-	Joubert syndrome (1)
1	-	-	Meckel syndrome, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.42
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.84	D
PhyloP100		1.3
Vest4		0.55
GERP RS		2.7
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs11230683; hg19: chr11-61165269;