11-61392635-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001173990.3(TMEM216):c.4C>G(p.Leu2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Transmembrane protein 216 (size 144) in uniprot entity TM216_HUMAN there are 12 pathogenic changes around while only 4 benign (75%) in NM_001173990.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17721164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM216	NM_001173990.3	c.4C>G	p.Leu2Val	missense_variant	1/5	ENST00000515837.7
TMEM216	NM_001173991.3	c.4C>G	p.Leu2Val	missense_variant	1/5
TMEM216	NM_001330285.2	c.-194C>G		5_prime_UTR_variant	1/5
TMEM216	NM_016499.6	c.-194C>G		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.4C>G	p.Leu2Val	missense_variant	1/5	2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 19, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TMEM216-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces leucine with valine at codon 2 of the TMEM216 protein (p.Leu2Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.29	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.14	N;N
REVEL	Benign	0.22
Sift	Benign	0.33	T;T
Sift4G	Benign	0.21	T;T
Vest4		0.29
MutPred		0.18		Gain of methylation at R4 (P = 0.1598);Gain of methylation at R4 (P = 0.1598);
MVP		0.67
MPC		0.13
ClinPred		0.15	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.088
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1554972407; hg19: chr11-61160107;