rs1057520085

Variant names:

• chr11-61393215-TGTGCTCCTTTTTCAG-T
• rs1057520085
• NM_001173990.3:c.35-13_36delGCTCCTTTTTCAGGT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001173991.3(TMEM216):​c.35-13_36delGCTCCTTTTTCAGGT​(p.Gly12fs) variant causes a frameshift, splice acceptor, splice region, 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G12G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: TMEM216 NM_001173991.3 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 1.00
• Publications: 0 publications found

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]

TMEM216 Gene-Disease associations (from GenCC):

• Joubert syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 38 pathogenic variants in the truncated region.
• 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 VariationId is 376902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173991.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	NM_001173990.3	MANE Select	c.35-13_36delGCTCCTTTTTCAGGT	p.Gly12fs	frameshift splice_acceptor splice_region intron	Exon 2 of 5	NP_001167461.1
	TMEM216	NM_016499.6		c.-149-13_-148delGCTCCTTTTTCAGGT		splice_region	Exon 2 of 5	NP_057583.2
	TMEM216	NM_001330285.2		c.-149-13_-148delGCTCCTTTTTCAGGT		splice_region	Exon 2 of 5	NP_001317214.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.35-15_35-1delGTGCTCCTTTTTCAG		splice_acceptor splice_region intron	N/A	ENSP00000440638.1
	TMEM216	ENST00000334888.10	TSL:2	c.35-15_35-1delGTGCTCCTTTTTCAG		splice_acceptor splice_region intron	N/A	ENSP00000334844.5
	TMEM216	ENST00000398979.7	TSL:1	c.-149-15_-149-1delGTGCTCCTTTTTCAG		splice_acceptor splice_region intron	N/A	ENSP00000381950.3

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

GnomAD2 exomes AF: 0.00000735 AC: 1 AN: 136096 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 31484

American (AMR) AF: 0.00 AC: 0 AN: 35596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25082

East Asian (EAS) AF: 0.00 AC: 0 AN: 35690

South Asian (SAS) AF: 0.00 AC: 0 AN: 79080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000651 AC: 7 AN: 1075100

Other (OTH) AF: 0.00 AC: 0 AN: 57738

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

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Joubert syndrome 2 (2)
1	-	-	Joubert syndrome (1)
1	-	-	Joubert syndrome 2;C1864148:Meckel syndrome, type 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=44/56	disease causing (long InDel)

Splicing

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

Other links and lift over

dbSNP: rs1057520085; hg19: chr11-61160687;