11-61392497-T-C

Variant names:

• chr11-61392497-T-C
• rs183785901
• ENST00000398979.7:c.-332T>C

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.-332T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000721 in 797,838 control chromosomes in the GnomAD database, including 3 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 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (3 hom.)
• Consequence: TMEM216 ENST00000398979.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.22
• 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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=-0.89).
• BP6: Variant 11-61392497-T-C is Benign according to our data. Variant chr11-61392497-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 305073.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000315 (48/152206) while in subpopulation EAS AF = 0.00913 (47/5150). AF 95% confidence interval is 0.00705. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000398979.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	NM_001173990.3	MANE Select	c.-135T>C		upstream_gene	N/A	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.-135T>C		upstream_gene	N/A	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.-332T>C		upstream_gene	N/A	NP_057583.2	Q9P0N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000398979.7	TSL:1	c.-332T>C		5_prime_UTR	Exon 1 of 5	ENSP00000381950.3	J3QT25
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.-135T>C		upstream_gene	N/A	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.-135T>C		upstream_gene	N/A	ENSP00000334844.5	Q9P0N5-3

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00911

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000816 AC: 527 AN: 645632 Hom.: 3 Cov.: 9 AF XY: 0.000838 AC XY: 281 AN XY: 335436

African (AFR) AF: 0.00 AC: 0 AN: 15836

American (AMR) AF: 0.00 AC: 0 AN: 21202

Ashkenazi Jewish (ASJ) AF: 0.000190 AC: 3 AN: 15764

East Asian (EAS) AF: 0.0158 AC: 508 AN: 32252

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2404

European-Non Finnish (NFE) AF: 0.00000452 AC: 2 AN: 442756

Other (OTH) AF: 0.000398 AC: 13 AN: 32630

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74412

African (AFR) AF: 0.00 AC: 0 AN: 41534

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

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

East Asian (EAS) AF: 0.00913 AC: 47 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000264

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Joubert syndrome 2 (1)
-	1	-	Meckel syndrome, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.34
PhyloP100		-3.2
PromoterAI		0.020	Neutral

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: rs183785901; hg19: chr11-61159969;