11-61392632-A-G

Variant summary

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

The NM_001173990.3(TMEM216):c.1A>G(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 0.00000291 in 1,375,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.427

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	UniProt
TMEM216	NM_001173990.3	c.1A>G	p.Met1?	start_lost	1/5	ENST00000515837.7
TMEM216	NM_001173991.3	c.1A>G	p.Met1?	start_lost	1/5
TMEM216	NM_001330285.2	c.-197A>G		5_prime_UTR_variant	1/5
TMEM216	NM_016499.6	c.-197A>G		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.1A>G	p.Met1?	start_lost	1/5	2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000743 AC: 1 AN: 134534 Hom.: 0 AF XY: 0.0000137 AC XY: 1 AN XY: 73242

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: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000291 AC: 4 AN: 1375952 Hom.: 0 Cov.: 32 AF XY: 0.00000294 AC XY: 2 AN XY: 679320

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: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 2;C1864148:Meckel syndrome, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	15
Dann	Benign	0.93
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	0.99	D;N;N
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.19
Sift	Benign	0.078	T;T
Sift4G	Benign	0.58	T;T
Vest4		0.19
MutPred		0.89		Gain of methylation at R4 (P = 0.2121);Gain of methylation at R4 (P = 0.2121);
MVP		0.62
ClinPred		0.083	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.39
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1287246452; hg19: chr11-61160104;