11-61392633-T-C

Variant names:

• chr11-61392633-T-C
• rs1554972406
• NM_001173990.3:c.2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001173990.3(TMEM216):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000326 in 1,535,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 start_lost
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.436
• 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: 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 61392653. Lost 0.050 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>C	p.Met1?	start_lost	Exon 1 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.2T>C	p.Met1?	start_lost	Exon 1 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.-196T>C		5_prime_UTR	Exon 1 of 5	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.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.2T>C	p.Met1?	start_lost	Exon 1 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.-196T>C		5_prime_UTR	Exon 1 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1383050 Hom.: 0 Cov.: 32 AF XY: 0.00000293 AC XY: 2 AN XY: 682520

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.0000280 AC: 1 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078264

Other (OTH) AF: 0.00 AC: 0 AN: 57878

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41594

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome 2;C1864148:Meckel syndrome, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.012	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.37	T
PhyloP100		-0.44
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.20
Sift	Benign	0.051	T
Sift4G	Benign	0.65	T
Vest4		0.069
MutPred		0.87		Gain of catalytic residue at M1 (P = 0.0178)
MVP		0.32
ClinPred		0.071	T
GERP RS		-2.1
PromoterAI		0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.15
gMVP		0.42
Mutation Taster		=107/93	polymorphism

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

Other links and lift over

dbSNP: rs1554972406; hg19: chr11-61160105;