rs557559653

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000398979.7(TMEM216):​c.-288G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,313,102 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 37 hom. )

Consequence

TMEM216
ENST00000398979.7 5_prime_UTR

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.232

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 11-61392541-G-A is Benign according to our data. Variant chr11-61392541-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305075.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000702 (107/152322) while in subpopulation SAS AF = 0.0192 (93/4834). AF 95% confidence interval is 0.0161. There are 2 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM216NM_001173990.3 linkc.-91G>A upstream_gene_variant ENST00000515837.7 NP_001167461.1 Q9P0N5-1
TMEM216NM_001173991.3 linkc.-91G>A upstream_gene_variant NP_001167462.1 Q9P0N5-3
TMEM216NM_016499.6 linkc.-288G>A upstream_gene_variant NP_057583.2 Q9P0N5-2
TMEM216NM_001330285.2 linkc.-288G>A upstream_gene_variant NP_001317214.1 Q9P0N5J3QT25

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM216ENST00000515837.7 linkc.-91G>A upstream_gene_variant 2 NM_001173990.3 ENSP00000440638.1 Q9P0N5-1
TMEM216ENST00000334888.10 linkc.-91G>A upstream_gene_variant 2 ENSP00000334844.5 Q9P0N5-3

Frequencies

GnomAD3 genomes
AF:
0.000703
AC:
107
AN:
152204
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.0192
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.000478
GnomAD4 exome
AF:
0.00129
AC:
1501
AN:
1160780
Hom.:
37
Cov.:
16
AF XY:
0.00196
AC XY:
1139
AN XY:
580894
show subpopulations
African (AFR)
AF:
0.0000379
AC:
1
AN:
26400
American (AMR)
AF:
0.0000923
AC:
3
AN:
32514
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
22564
East Asian (EAS)
AF:
0.00
AC:
0
AN:
34708
South Asian (SAS)
AF:
0.0191
AC:
1390
AN:
72678
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
33042
Middle Eastern (MID)
AF:
0.00210
AC:
8
AN:
3808
European-Non Finnish (NFE)
AF:
0.0000588
AC:
52
AN:
884952
Other (OTH)
AF:
0.000938
AC:
47
AN:
50114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.503
Heterozygous variant carriers
0
75
150
226
301
376
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20
40
60
80
100
<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:
0.000702
AC:
107
AN:
152322
Hom.:
2
Cov.:
32
AF XY:
0.00113
AC XY:
84
AN XY:
74482
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41570
American (AMR)
AF:
0.00
AC:
0
AN:
15298
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000194
AC:
1
AN:
5166
South Asian (SAS)
AF:
0.0192
AC:
93
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.000147
AC:
10
AN:
68032
Other (OTH)
AF:
0.000473
AC:
1
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
5
10
16
21
26
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.000416
Hom.:
0
Bravo
AF:
0.000196
Asia WGS
AF:
0.00953
AC:
33
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Meckel syndrome, type 2 Uncertain:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Joubert syndrome 2 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
1.9
DANN
Benign
0.87
PhyloP100
-0.23
PromoterAI
-0.098
Neutral
Mutation Taster
=298/2
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

Publications

Other links and lift over

dbSNP: rs557559653; hg19: chr11-61160013; API