rs111371929

chr11-61398297-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001173990.3(TMEM216):c.*21A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,610,568 control chromosomes in the GnomAD database, including 62 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 0.0059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (61 hom.)
• Consequence: TMEM216 NM_001173990.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.0550

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-61398297-A-G is Benign according to our data. Variant chr11-61398297-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257594.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0059 (898/152316) while in subpopulation NFE AF= 0.01 (682/68030). AF 95% confidence interval is 0.0094. There are 1 homozygotes in gnomad4. There are 382 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM216	NM_001173990.3	c.*21A>G		3_prime_UTR_variant	5/5	ENST00000515837.7
TMEM216	NM_001173991.3	c.*21A>G		3_prime_UTR_variant	5/5
TMEM216	NM_001330285.2	c.*21A>G		3_prime_UTR_variant	5/5
TMEM216	NM_016499.6	c.*21A>G		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.*21A>G		3_prime_UTR_variant	5/5	2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes AF: 0.00590 AC: 898 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00500 AC: 1229 AN: 245600 Hom.: 14 AF XY: 0.00508 AC XY: 676 AN XY: 133176

Gnomad AFR exome AF: 0.00145

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.00127

Gnomad NFE exome AF: 0.00925

Gnomad OTH exome AF: 0.00419

GnomAD4 exome AF: 0.00770 AC: 11226 AN: 1458252 Hom.: 61 Cov.: 31 AF XY: 0.00742 AC XY: 5383 AN XY: 725314

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.000269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00942

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00590 AC: 898 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00513 AC XY: 382 AN XY: 74480

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0100

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00743 Hom.: 0

Bravo AF: 0.00600

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	TMEM216: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2020	- -

Meckel syndrome, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Joubert syndrome 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.50
Cadd	Benign	8.4
Dann	Benign	0.86

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

LitVar

Other links and lift over

dbSNP: rs111371929; hg19: chr11-61165769;