NM_001173990.3:c.140T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001173990.3(TMEM216):c.140T>C(p.Val47Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000712 in 1,612,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 2 hom. )

Consequence

TMEM216
NM_001173990.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 3.65

Publications

2 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):

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

TMEM216 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03314331).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM216	NM_001173990.3	MANE Select	c.140T>C	p.Val47Ala	missense	Exon 3 of 5	NP_001167461.1	Q9P0N5-1
TMEM216	NM_001173991.3		c.140T>C	p.Val47Ala	missense	Exon 3 of 5	NP_001167462.1	Q9P0N5-3
TMEM216	NM_016499.6		c.-44T>C		5_prime_UTR	Exon 3 of 5	NP_057583.2	Q9P0N5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.140T>C	p.Val47Ala	missense	Exon 3 of 5	ENSP00000440638.1	Q9P0N5-1
TMEM216	ENST00000334888.10	TSL:2	c.140T>C	p.Val47Ala	missense	Exon 3 of 5	ENSP00000334844.5	Q9P0N5-3
TMEM216	ENST00000398979.7	TSL:1	c.-44T>C		5_prime_UTR	Exon 3 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes

AF:

0.000539

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000595

AC:

147

AN:

247036

AF XY:

0.000558

show subpopulations

Gnomad AFR exome

AF:

0.000264

Gnomad AMR exome

AF:

0.00169

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000724

Gnomad OTH exome

AF:

0.000671

GnomAD4 exome

AF:

0.000730

AC:

1066

AN:

1460544

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

509

AN XY:

726590

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33464

American (AMR)

AF:

0.00157

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000871

AC:

968

AN:

1111334

Other (OTH)

AF:

0.000398

AC:

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000538

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41576

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000491

Hom.:

Bravo

AF:

0.000604

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ExAC

AF:

0.000546

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.00113

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Joubert syndrome 2 (2)

Joubert syndrome 2;C1864148:Meckel syndrome, type 2 (2)

Joubert syndrome (1)

Meckel syndrome, type 2 (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.29

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.58

M_CAP

Benign

0.038

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.72

PhyloP100

3.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.93

REVEL

Uncertain

0.37

Sift

Benign

0.12

Sift4G

Benign

0.38

Vest4

0.26

MVP

0.61

MPC

0.17

ClinPred

0.021

GERP RS

6.0

Varity_R

0.098

gMVP

0.41

Mutation Taster

=81/19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over