NM_001173990.3:c.-2G>T

Variant names:

• chr11-61392630-G-T
• rs7107543
• NM_001173990.3:c.-2G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001173990.3(TMEM216):​c.-2G>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 0.014 in 1,535,262 control chromosomes in the GnomAD database, including 2,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (1429 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (1182 hom.)
• Consequence: TMEM216 NM_001173990.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.83
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-61392630-G-T is Benign according to our data. Variant chr11-61392630-G-T is described in ClinVar as [Benign]. Clinvar id is 193188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.-2G>T		5_prime_UTR_variant	Exon 1 of 5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.-2G>T		5_prime_UTR_variant	Exon 1 of 5		NP_001167462.1
TMEM216	NM_016499.6	c.-199G>T		5_prime_UTR_variant	Exon 1 of 5		NP_057583.2
TMEM216	NM_001330285.2	c.-199G>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.-2G>T		5_prime_UTR_variant	Exon 1 of 5	2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.-2G>T		5_prime_UTR_variant	Exon 1 of 5	2		ENSP00000334844.5

Frequencies

GnomAD3 genomes AF: 0.0738 AC: 11223 AN: 152108 Hom.: 1415 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0157 AC: 2117 AN: 134498 AF XY: 0.0118

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000952

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00918

GnomAD4 exome AF: 0.00739 AC: 10223 AN: 1383034 Hom.: 1182 Cov.: 32 AF XY: 0.00637 AC XY: 4350 AN XY: 682482

African (AFR) AF: 0.264 AC: 8338 AN: 31562

American (AMR) AF: 0.0144 AC: 514 AN: 35690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35720

South Asian (SAS) AF: 0.000669 AC: 53 AN: 79216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33864

Middle Eastern (MID) AF: 0.00765 AC: 43 AN: 5624

European-Non Finnish (NFE) AF: 0.000182 AC: 196 AN: 1078336

Other (OTH) AF: 0.0186 AC: 1078 AN: 57854

GnomAD4 genome AF: 0.0741 AC: 11274 AN: 152228 Hom.: 1429 Cov.: 32 AF XY: 0.0719 AC XY: 5350 AN XY: 74434

African (AFR) AF: 0.257 AC: 10676 AN: 41508

American (AMR) AF: 0.0279 AC: 427 AN: 15296

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

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

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68012

Other (OTH) AF: 0.0545 AC: 115 AN: 2112

Alfa AF: 0.0209 Hom.: 131

Bravo AF: 0.0834

Asia WGS AF: 0.0190 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 2 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Meckel syndrome, type 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Joubert syndrome Benign:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.84
PhyloP100		1.8
PromoterAI		-0.095	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7107543; hg19: chr11-61160102;