chr16-75556194-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001077418.3(TMEM231):ā€‹c.16C>Gā€‹(p.Leu6Val) variant causes a missense change. The variant allele was found at a frequency of 0.0938 in 1,485,022 control chromosomes in the GnomAD database, including 19,435 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.12 ( 2663 hom., cov: 33)
Exomes š‘“: 0.091 ( 16772 hom. )

Consequence

TMEM231
NM_001077418.3 missense

Scores

16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.96
Variant links:
Genes affected
TMEM231 (HGNC:37234): (transmembrane protein 231) This gene encodes a transmembrane protein, which is a component of the B9 complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. Mutations in this gene cause Joubert syndrome (JBTS). Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.8012524E-5).
BP6
Variant 16-75556194-G-C is Benign according to our data. Variant chr16-75556194-G-C is described in ClinVar as [Benign]. Clinvar id is 130587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.691 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TMEM231NM_001077418.3 linkc.16C>G p.Leu6Val missense_variant Exon 1 of 7 ENST00000258173.11 NP_001070886.1 Q9H6L2-1
TMEM231NM_001077416.2 linkc.78C>G p.Ser26Arg missense_variant Exon 1 of 6 NP_001070884.2 Q9H6L2
TMEM231NR_074083.2 linkn.59C>G non_coding_transcript_exon_variant Exon 1 of 7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TMEM231ENST00000258173.11 linkc.16C>G p.Leu6Val missense_variant Exon 1 of 7 1 NM_001077418.3 ENSP00000258173.5 Q9H6L2-1
TMEM231ENST00000568377.5 linkc.6C>G p.Ser2Arg missense_variant Exon 1 of 6 1 ENSP00000476267.1 Q9H6L2-2
TMEM231ENST00000565067.5 linkc.16C>G p.Leu6Val missense_variant Exon 1 of 6 5 ENSP00000457254.1 H3BTN6
TMEM231ENST00000562410.5 linkn.16C>G non_coding_transcript_exon_variant Exon 1 of 7 1 ENSP00000454582.1 H3BMW7
TMEM231ENST00000570006.5 linkn.16C>G non_coding_transcript_exon_variant Exon 1 of 7 5 ENSP00000455520.1 H3BPY4

Frequencies

GnomAD3 genomes
AF:
0.119
AC:
18175
AN:
152146
Hom.:
2652
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0929
Gnomad AMI
AF:
0.106
Gnomad AMR
AF:
0.292
Gnomad ASJ
AF:
0.137
Gnomad EAS
AF:
0.709
Gnomad SAS
AF:
0.305
Gnomad FIN
AF:
0.0581
Gnomad MID
AF:
0.0633
Gnomad NFE
AF:
0.0477
Gnomad OTH
AF:
0.126
GnomAD3 exomes
AF:
0.210
AC:
24008
AN:
114184
Hom.:
5411
AF XY:
0.196
AC XY:
12479
AN XY:
63530
show subpopulations
Gnomad AFR exome
AF:
0.103
Gnomad AMR exome
AF:
0.438
Gnomad ASJ exome
AF:
0.146
Gnomad EAS exome
AF:
0.751
Gnomad SAS exome
AF:
0.312
Gnomad FIN exome
AF:
0.0584
Gnomad NFE exome
AF:
0.0520
Gnomad OTH exome
AF:
0.158
GnomAD4 exome
AF:
0.0908
AC:
121014
AN:
1332758
Hom.:
16772
Cov.:
31
AF XY:
0.0945
AC XY:
61597
AN XY:
651754
show subpopulations
Gnomad4 AFR exome
AF:
0.0918
Gnomad4 AMR exome
AF:
0.399
Gnomad4 ASJ exome
AF:
0.120
Gnomad4 EAS exome
AF:
0.719
Gnomad4 SAS exome
AF:
0.274
Gnomad4 FIN exome
AF:
0.0551
Gnomad4 NFE exome
AF:
0.0486
Gnomad4 OTH exome
AF:
0.123
GnomAD4 genome
AF:
0.120
AC:
18216
AN:
152264
Hom.:
2663
Cov.:
33
AF XY:
0.132
AC XY:
9802
AN XY:
74438
show subpopulations
Gnomad4 AFR
AF:
0.0934
Gnomad4 AMR
AF:
0.293
Gnomad4 ASJ
AF:
0.137
Gnomad4 EAS
AF:
0.710
Gnomad4 SAS
AF:
0.304
Gnomad4 FIN
AF:
0.0581
Gnomad4 NFE
AF:
0.0477
Gnomad4 OTH
AF:
0.127
Alfa
AF:
0.0786
Hom.:
1200
Bravo
AF:
0.140
TwinsUK
AF:
0.0464
AC:
172
ALSPAC
AF:
0.0467
AC:
180
ESP6500AA
AF:
0.0835
AC:
301
ESP6500EA
AF:
0.0463
AC:
361
ExAC
AF:
0.156
AC:
17902
Asia WGS
AF:
0.449
AC:
1557
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 02, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joubert syndrome 20;C3809352:Meckel syndrome, type 11 Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Joubert syndrome 20 Benign:1
May 28, 2019
Mendelics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
17
DANN
Benign
0.88
DEOGEN2
Benign
0.060
T;T
Eigen
Benign
-0.038
Eigen_PC
Benign
0.11
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.83
T;T
MetaRNN
Benign
0.000018
T;T
MetaSVM
Benign
-0.92
T
PROVEAN
Benign
0.86
N;N
REVEL
Benign
0.099
Sift
Benign
1.0
T;T
Sift4G
Benign
0.78
T;T
Polyphen
0.021
B;.
Vest4
0.045
ClinPred
0.075
T
GERP RS
4.6
Varity_R
0.11
gMVP
0.46

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3743601; hg19: chr16-75590092; COSMIC: COSV50738700; COSMIC: COSV50738700; API