Genetic Variant TMEM216:p.Arg4Pro (chr11-61392642-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001173990.3(TMEM216):c.11G>C(p.Arg4Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TMEM216
NM_001173990.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.39

Publications

0 publications found

Variant links:

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

TMEM216 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23023772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3 link	c.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 5	ENST00000515837.7	NP_001167461.1	Q9P0N5-1
TMEM216	NM_001173991.3 link	c.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 5		NP_001167462.1	Q9P0N5-3
TMEM216	NM_016499.6 link	c.-187G>C		5_prime_UTR_variant	Exon 1 of 5		NP_057583.2	Q9P0N5-2
TMEM216	NM_001330285.2 link	c.-187G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001317214.1	Q9P0N5J3QT25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7 link	c.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 5	2	NM_001173990.3	ENSP00000440638.1		Q9P0N5-1
TMEM216	ENST00000334888.10 link	c.11G>C	p.Arg4Pro	missense_variant	Exon 1 of 5	2		ENSP00000334844.5		Q9P0N5-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1362036

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

672728

African (AFR)

AF:

0.00

AC:

AN:

30882

American (AMR)

AF:

0.00

AC:

AN:

35084

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24138

East Asian (EAS)

AF:

0.00

AC:

AN:

33772

South Asian (SAS)

AF:

0.00

AC:

AN:

79040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1065604

Other (OTH)

AF:

0.00

AC:

AN:

56206

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.46

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.23

T;T

MetaSVM

Uncertain

0.056

MutationAssessor

Benign

0.55

N;N

PhyloP100

5.4

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.040

N;N

REVEL

Uncertain

0.42

Sift

Benign

0.22

T;T

Sift4G

Benign

0.24

T;T

Vest4

0.33

MutPred

0.25

Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);

MVP

0.61

MPC

0.19

ClinPred

0.64

GERP RS

5.6

PromoterAI

0.036

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.29

gMVP

0.44

Mutation Taster

=75/25

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over