11-61393887-T-G

Position:

• chr11-61393887-T-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.140T>G​(p.Val47Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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 7 pathogenic changes around while only 1 benign (88%) in NM_001173990.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24289787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.140T>G	p.Val47Gly	missense_variant	3/5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.140T>G	p.Val47Gly	missense_variant	3/5		NP_001167462.1
TMEM216	NM_001330285.2	c.-44T>G		5_prime_UTR_variant	3/5		NP_001317214.1
TMEM216	NM_016499.6	c.-44T>G		5_prime_UTR_variant	3/5		NP_057583.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.140T>G	p.Val47Gly	missense_variant	3/5	2	NM_001173990.3	ENSP00000440638	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460546 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726590

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: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000993 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.11	T;T
Vest4		0.36
MVP		0.64
MPC		0.23
ClinPred		0.14	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.54

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: rs762918371; hg19: chr11-61161359; COSMIC: COSV58425876;