chr11-61392606-TGCTCCGGGAGCCGCTGTGGCAGCGTATGCTGCCACG-T

Position:

• chr11-61392606-TGCTCCGGGAGCCGCTGTGGCAGCGTATGCTGCCACG-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001173990.3(TMEM216):​c.-24_12del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM216 NM_001173990.3 start_lost, 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.84

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.-24_12del		start_lost, 5_prime_UTR_variant	1/5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.-24_12del		start_lost, 5_prime_UTR_variant	1/5		NP_001167462.1
TMEM216	NM_001330285.2	c.-221_-186del		5_prime_UTR_variant	1/5		NP_001317214.1
TMEM216	NM_016499.6	c.-221_-186del		5_prime_UTR_variant	1/5		NP_057583.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.-24_12del		start_lost, 5_prime_UTR_variant	1/5	2	NM_001173990.3	ENSP00000440638	P4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 02, 2017

- -

Familial aplasia of the vermis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2020

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. Disruption of the initiator codon has not been reported in the literature in individuals with TMEM216-related conditions. ClinVar contains an entry for this variant (Variation ID: 502365). 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 affects the initiator methionine of the TMEM216 mRNA. The next in-frame methionine is located at codon 8. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554972391; hg19: chr11-61160078;