11-61393977-GT-CG

Variant names:

• chr11-61393977-GT-CG
• NM_001173990.3:c.229+1_229+2delGTinsCG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_001173990.3(TMEM216):​c.229+1_229+2delGTinsCG variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM216 NM_001173990.3 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.70
• 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia
• Joubert syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.21232876 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of -19, new splice context is: gaaGTaatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173990.3. 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.229+1_229+2delGTinsCG		splice_donor intron	N/A	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.229+1_229+2delGTinsCG		splice_donor intron	N/A	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.46+1_46+2delGTinsCG		splice_donor intron	N/A	NP_057583.2	Q9P0N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.229+1_229+2delGTinsCG		splice_donor intron	N/A	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.229+1_229+2delGTinsCG		splice_donor intron	N/A	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.46+1_46+2delGTinsCG		splice_donor intron	N/A	ENSP00000381950.3	J3QT25

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-61161449;