NM_001173990.3:c.217C>T

Variant names:

• chr11-61393964-C-T
• rs779526456
• NM_001173990.3:c.217C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001173990.3(TMEM216):​c.217C>T​(p.Arg73Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,604 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 0.928
• Publications: 6 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):

• 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 11 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, 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 chr11-61393965-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 11-61393964-C-T is Pathogenic according to our data. Variant chr11-61393964-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217705.

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.217C>T	p.Arg73Cys	missense	Exon 3 of 5	NP_001167461.1
	TMEM216	NM_001173991.3		c.217C>T	p.Arg73Cys	missense	Exon 3 of 5	NP_001167462.1
	TMEM216	NM_016499.6		c.34C>T	p.Arg12Cys	missense	Exon 3 of 5	NP_057583.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.217C>T	p.Arg73Cys	missense	Exon 3 of 5	ENSP00000440638.1
	TMEM216	ENST00000334888.10	TSL:2	c.217C>T	p.Arg73Cys	missense	Exon 3 of 5	ENSP00000334844.5
	TMEM216	ENST00000398979.7	TSL:1	c.34C>T	p.Arg12Cys	missense	Exon 3 of 5	ENSP00000381950.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249232 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461604 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111792

Other (OTH) AF: 0.0000331 AC: 2 AN: 60368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Joubert syndrome 2 (2)
1	1	-	not provided (2)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.93
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.98
MVP		0.83
MPC		0.70
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.91
Mutation Taster		=6/94	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: rs779526456; hg19: chr11-61161436; COSMIC: COSV100609944;