11-61392608-C-T

Variant names:

• chr11-61392608-C-T
• rs59493015
• NM_001173990.3:c.-24C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001173990.3(TMEM216):​c.-24C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,535,426 control chromosomes in the GnomAD database, including 2 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 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: TMEM216 NM_001173990.3 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.654
• Publications: 2 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 11-61392608-C-T is Benign according to our data. Variant chr11-61392608-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305076.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.-24C>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.-24C>T		5_prime_UTR_variant	Exon 1 of 5		NP_001167462.1
TMEM216	NM_016499.6	c.-221C>T		5_prime_UTR_variant	Exon 1 of 5		NP_057583.2
TMEM216	NM_001330285.2	c.-221C>T		5_prime_UTR_variant	Exon 1 of 5		NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.-24C>T		5_prime_UTR_variant	Exon 1 of 5	2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.-24C>T		5_prime_UTR_variant	Exon 1 of 5	2		ENSP00000334844.5

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000342 AC: 46 AN: 134376 AF XY: 0.000342

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.0000410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.000567

Gnomad OTH exome AF: 0.000726

GnomAD4 exome AF: 0.000410 AC: 567 AN: 1383114 Hom.: 2 Cov.: 31 AF XY: 0.000418 AC XY: 285 AN XY: 682492

African (AFR) AF: 0.0000634 AC: 2 AN: 31558

American (AMR) AF: 0.00 AC: 0 AN: 35620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35728

South Asian (SAS) AF: 0.000151 AC: 12 AN: 79212

European-Finnish (FIN) AF: 0.00171 AC: 58 AN: 33874

Middle Eastern (MID) AF: 0.000546 AC: 3 AN: 5490

European-Non Finnish (NFE) AF: 0.000438 AC: 472 AN: 1078606

Other (OTH) AF: 0.000346 AC: 20 AN: 57854

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74470

African (AFR) AF: 0.0000962 AC: 4 AN: 41572

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000295

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 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. -

Joubert syndrome 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 specified Benign:1

Jul 21, 2016

GeneDx

Significance: Likely 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. -

TMEM216-related disorder Benign:1

May 25, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		0.65
PromoterAI		0.53	Over-expression
Mutation Taster		=297/3	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: rs59493015; hg19: chr11-61160080;