chr11-61393965-G-T

Variant names:

• chr11-61393965-G-T
• rs201108965
• NM_001173990.3:c.218G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM2 PM5 PP5_Very_Strong

The NM_001173990.3(TMEM216):​c.218G>T​(p.Arg73Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001365595: In vitro functional studies provide some evidence that this variant impacts protein function (Valente 2010)" and additional evidence is available in ClinVar. 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 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: 6.70
• Publications: 31 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 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001365595: In vitro functional studies provide some evidence that this variant impacts protein function (Valente 2010); SCV000322115: Published functional studies have reported a significant decrease in TMEM216 protein production in cells transfected with R73L compared to the wild type and ciliogenesis disruption in TMEM216-R73L mutated fibroblasts in affected individuals (Lee et al., 2012; Valente et al., 2010); SCV000554071: Experimental studies have shown that this missense change affects TMEM216 function (PMID: 20512146, 22282472).; SCV000741987: Functional analysis on patient fibroblasts demonstrated the p.R73L alteration disrupted ciliogenesis (Lee, 2012).; SCV000915533: Lee et al. (2012) reported that fibroblasts from a patient carrying the p.Arg73Leu variant showed failure of ciliogenesis. PMID:22383716
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 chr11-61393964-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217705.
• PP5: Variant 11-61393965-G-T is Pathogenic according to our data. Variant chr11-61393965-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 197.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.218G>T	p.Arg73Leu	missense	Exon 3 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.218G>T	p.Arg73Leu	missense	Exon 3 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.35G>T	p.Arg12Leu	missense	Exon 3 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.218G>T	p.Arg73Leu	missense	Exon 3 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.218G>T	p.Arg73Leu	missense	Exon 3 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.35G>T	p.Arg12Leu	missense	Exon 3 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000173 AC: 43 AN: 249228 AF XY: 0.000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000122 AC: 179 AN: 1461606 Hom.: 0 Cov.: 30 AF XY: 0.000128 AC XY: 93 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 127 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111798

Other (OTH) AF: 0.000315 AC: 19 AN: 60366

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Joubert syndrome 2 (8)
5	-	-	not provided (5)
2	-	-	TMEM216-related disorder (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome 2;C1864148:Meckel syndrome, type 2 (1)
1	-	-	Meckel syndrome, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Vest4		0.98
MVP		0.75
MPC		0.66
ClinPred		0.39	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.93
gMVP		0.93
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs201108965; hg19: chr11-61161437; COSMIC: COSV58426505;