11-61392546-G-A

Variant names:

• chr11-61392546-G-A
• rs188478638
• ENST00000398979.7:c.-283G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000398979.7(TMEM216):​c.-283G>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 0.000743 in 1,342,780 control chromosomes in the GnomAD database, including 20 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 0.00055 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (19 hom.)
• Consequence: TMEM216 ENST00000398979.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.942
• 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):

• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 11-61392546-G-A is Benign according to our data. Variant chr11-61392546-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 878887.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000545 (83/152264) while in subpopulation SAS AF = 0.012 (58/4824). AF 95% confidence interval is 0.00955. There are 1 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.-86G>A		upstream_gene_variant		ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.-86G>A		upstream_gene_variant			NP_001167462.1
TMEM216	NM_016499.6	c.-283G>A		upstream_gene_variant			NP_057583.2
TMEM216	NM_001330285.2	c.-283G>A		upstream_gene_variant			NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.-86G>A		upstream_gene_variant		2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.-86G>A		upstream_gene_variant		2		ENSP00000334844.5

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000769 AC: 915 AN: 1190516 Hom.: 19 Cov.: 17 AF XY: 0.00106 AC XY: 629 AN XY: 594666

African (AFR) AF: 0.0000371 AC: 1 AN: 26982

American (AMR) AF: 0.000583 AC: 19 AN: 32566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22960

East Asian (EAS) AF: 0.00 AC: 0 AN: 34830

South Asian (SAS) AF: 0.00991 AC: 734 AN: 74104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33242

Middle Eastern (MID) AF: 0.00229 AC: 9 AN: 3924

European-Non Finnish (NFE) AF: 0.000102 AC: 93 AN: 910818

Other (OTH) AF: 0.00115 AC: 59 AN: 51090

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.000793 AC XY: 59 AN XY: 74434

African (AFR) AF: 0.0000481 AC: 2 AN: 41556

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000234

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Meckel syndrome, type 2 Uncertain:1

Jan 13, 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. -

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TMEM216: BS1 -

Joubert syndrome 2 Benign:1

Jan 13, 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	-0.76
CADD	Benign	1.3
DANN	Benign	0.90
PhyloP100		-0.94
PromoterAI		-0.013	Neutral
Mutation Taster		=296/4	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

Other links and lift over

dbSNP: rs188478638; hg19: chr11-61160018;