chr11-61397808-G-A

Variant names:

• chr11-61397808-G-A
• rs3741265
• NM_001173990.3:c.264G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001173990.3(TMEM216):​c.264G>A​(p.Pro88Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.859 in 1,613,466 control chromosomes in the GnomAD database, including 595,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P88P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.84 (54411 hom., cov: 32)
  • Exomes 𝑓: 0.86 (541421 hom.)
• Consequence: TMEM216 NM_001173990.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.97
• Publications: 33 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, STRONG Submitted by: ClinGen, PanelApp Australia
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 11-61397808-G-A is Benign according to our data. Variant chr11-61397808-G-A is described in ClinVar as Benign. ClinVar VariationId is 126296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173990.3. 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.264G>A	p.Pro88Pro	synonymous	Exon 4 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.264G>A	p.Pro88Pro	synonymous	Exon 4 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.81G>A	p.Pro27Pro	synonymous	Exon 4 of 5	NP_057583.2	Q9P0N5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM216	ENST00000515837.7	TSL:2 MANE Select	c.264G>A	p.Pro88Pro	synonymous	Exon 4 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.264G>A	p.Pro88Pro	synonymous	Exon 4 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.81G>A	p.Pro27Pro	synonymous	Exon 4 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes AF: 0.844 AC: 128384 AN: 152080 Hom.: 54388 Cov.: 32

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.873

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.975

Gnomad SAS AF: 0.857

Gnomad FIN AF: 0.887

Gnomad MID AF: 0.899

Gnomad NFE AF: 0.861

Gnomad OTH AF: 0.864

GnomAD2 exomes AF: 0.871 AC: 216972 AN: 249036 AF XY: 0.872

Gnomad AFR exome AF: 0.760

Gnomad AMR exome AF: 0.888

Gnomad ASJ exome AF: 0.896

Gnomad EAS exome AF: 0.967

Gnomad FIN exome AF: 0.882

Gnomad NFE exome AF: 0.863

Gnomad OTH exome AF: 0.878

GnomAD4 exome AF: 0.860 AC: 1256957 AN: 1461268 Hom.: 541421 Cov.: 56 AF XY: 0.861 AC XY: 626049 AN XY: 726934

African (AFR) AF: 0.760 AC: 25441 AN: 33472

American (AMR) AF: 0.887 AC: 39682 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 23333 AN: 26130

East Asian (EAS) AF: 0.973 AC: 38640 AN: 39700

South Asian (SAS) AF: 0.869 AC: 74916 AN: 86234

European-Finnish (FIN) AF: 0.884 AC: 47196 AN: 53396

Middle Eastern (MID) AF: 0.894 AC: 4931 AN: 5516

European-Non Finnish (NFE) AF: 0.855 AC: 950350 AN: 1111752

Other (OTH) AF: 0.869 AC: 52468 AN: 60344

GnomAD4 genome AF: 0.844 AC: 128458 AN: 152198 Hom.: 54411 Cov.: 32 AF XY: 0.848 AC XY: 63090 AN XY: 74404

African (AFR) AF: 0.769 AC: 31888 AN: 41488

American (AMR) AF: 0.874 AC: 13361 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3113 AN: 3470

East Asian (EAS) AF: 0.975 AC: 5045 AN: 5174

South Asian (SAS) AF: 0.857 AC: 4138 AN: 4828

European-Finnish (FIN) AF: 0.887 AC: 9406 AN: 10604

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.861 AC: 58598 AN: 68020

Other (OTH) AF: 0.857 AC: 1814 AN: 2116

Alfa AF: 0.853 Hom.: 87077

Bravo AF: 0.838

Asia WGS AF: 0.876 AC: 3046 AN: 3478

EpiCase AF: 0.866

EpiControl AF: 0.863

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Joubert syndrome 2 (3)
-	-	3	not provided (3)
-	-	2	Meckel syndrome, type 2 (2)
-	-	1	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.46
DANN	Benign	0.66
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3741265; hg19: chr11-61165280; COSMIC: COSV108172421; COSMIC: COSV108172421;