rs762918371

Variant names:

• chr11-61393887-T-C
• rs762918371
• NM_001173990.3:c.140T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-61393887-T-C
• chr11-61393887-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_001173990.3(TMEM216):​c.140T>C​(p.Val47Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000712 in 1,612,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (2 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• 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 Likely_benign. Variant got -6 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.03314331).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 5		NP_001167462.1
TMEM216	NM_016499.6	c.-44T>C		5_prime_UTR_variant	Exon 3 of 5		NP_057583.2
TMEM216	NM_001330285.2	c.-44T>C		5_prime_UTR_variant	Exon 3 of 5		NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 5	2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.140T>C	p.Val47Ala	missense_variant	Exon 3 of 5	2		ENSP00000334844.5

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000595 AC: 147 AN: 247036 Hom.: 0 AF XY: 0.000558 AC XY: 75 AN XY: 134378

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000724

Gnomad OTH exome AF: 0.000671

GnomAD4 exome AF: 0.000730 AC: 1066 AN: 1460544 Hom.: 2 Cov.: 30 AF XY: 0.000701 AC XY: 509 AN XY: 726590

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000871

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000538 AC: 82 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 39 AN XY: 74504

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000789 Hom.: 0

Bravo AF: 0.000604

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.000546 AC: 66

EpiCase AF: 0.000437

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Jun 13, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2024

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joubert syndrome 2 Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Apr 14, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Meckel syndrome, type 2 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Joubert syndrome 2;C1864148:Meckel syndrome, type 2 Uncertain:1

May 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial aplasia of the vermis Uncertain:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 47 of the TMEM216 protein (p.Val47Ala). This variant is present in population databases (rs762918371, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of inherited retinal disorder (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 289981). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Retinal dystrophy Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.77
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.72	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.93	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.12	T;T
Sift4G	Benign	0.38	T;T
Vest4		0.26
MVP		0.61
MPC		0.17
ClinPred		0.021	T
GERP RS		6.0
Varity_R		0.098
gMVP		0.41

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;