11-61392642-G-A

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.11G>A(p.Arg4Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000139 in 1,513,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.39

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=0.15406898).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM216	NM_001173990.3	c.11G>A	p.Arg4Gln	missense_variant	1/5	ENST00000515837.7
TMEM216	NM_001173991.3	c.11G>A	p.Arg4Gln	missense_variant	1/5
TMEM216	NM_001330285.2	c.-187G>A		5_prime_UTR_variant	1/5
TMEM216	NM_016499.6	c.-187G>A		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.11G>A	p.Arg4Gln	missense_variant	1/5	2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151776 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 18 AN: 1362038 Hom.: 0 Cov.: 32 AF XY: 0.0000149 AC XY: 10 AN XY: 672730

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000160

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151896 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74264

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2023

The c.11G>A (p.R4Q) alteration is located in exon 1 (coding exon 1) of the TMEM216 gene. This alteration results from a G to A substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Joubert syndrome 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4 of the TMEM216 protein (p.Arg4Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TMEM216-related conditions. ClinVar contains an entry for this variant (Variation ID: 855127). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	0.037
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.56	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.20	N;N
REVEL	Uncertain	0.45
Sift	Benign	0.38	T;T
Sift4G	Benign	0.46	T;T
Vest4		0.29
MutPred		0.20		Loss of MoRF binding (P = 0.0017);Loss of MoRF binding (P = 0.0017);
MVP		0.70
MPC		0.15
ClinPred		0.86	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.19
gMVP		0.21

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

Other links and lift over

dbSNP: rs548299486; hg19: chr11-61160114;