NM_001173990.3:c.7C>A

Variant names:

• chr11-61392638-C-A
• rs1554972409
• NM_001173990.3:c.7C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001173990.3(TMEM216):​c.7C>A​(p.Pro3Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000651 in 1,382,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.24
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4115949).

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.7C>A	p.Pro3Thr	missense	Exon 1 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.7C>A	p.Pro3Thr	missense	Exon 1 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.-191C>A		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.7C>A	p.Pro3Thr	missense	Exon 1 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.7C>A	p.Pro3Thr	missense	Exon 1 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.-191C>A		5_prime_UTR	Exon 1 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000651 AC: 9 AN: 1382034 Hom.: 0 Cov.: 32 AF XY: 0.0000117 AC XY: 8 AN XY: 682044

African (AFR) AF: 0.00 AC: 0 AN: 31542

American (AMR) AF: 0.00 AC: 0 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.00 AC: 0 AN: 35604

South Asian (SAS) AF: 0.0000757 AC: 6 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078020

Other (OTH) AF: 0.00 AC: 0 AN: 57772

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome (1)
-	1	-	Joubert syndrome 2 (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
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.55	N
PhyloP100		4.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.48
MutPred		0.16		Gain of helix (P = 0.0496)
MVP		0.57
MPC		0.61
ClinPred		0.91	D
GERP RS		5.6
PromoterAI		0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.41
gMVP		0.55
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554972409; hg19: chr11-61160110;