rs1057520085

chr11-61393215-TGTGCTCCTTTTTCAG-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001173990.3(TMEM216):c.35-13_36del variant causes a splice acceptor, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000522 in 1,531,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.00

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 14 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.2305936 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-61393215-TGTGCTCCTTTTTCAG-T is Pathogenic according to our data. Variant chr11-61393215-TGTGCTCCTTTTTCAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM216	NM_001173990.3	c.35-13_36del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000515837.7
TMEM216	NM_001173991.3	c.35-13_36del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant
TMEM216	NM_001330285.2	c.-149-13_-148del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant
TMEM216	NM_016499.6	c.-149-13_-148del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.35-13_36del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000735 AC: 1 AN: 136096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 73920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000508 AC: 7 AN: 1379308 Hom.: 0 AF XY: 0.00000441 AC XY: 3 AN XY: 680914

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: 0.00

Gnomad4 NFE exome AF: 0.00000651

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 2 Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 08, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 10, 2023	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 09, 2017

- -

Familial aplasia of the vermis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 11, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 376902). This variant has not been reported in the literature in individuals affected with TMEM216-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant results in the deletion of part of exon 2 (c.35-13_36del) of the TMEM216 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TMEM216 are known to be pathogenic (PMID: 20512146). -

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: rs1057520085; hg19: chr11-61160687;