chr11-61398297-A-G

Variant names:

• chr11-61398297-A-G
• rs111371929
• NM_001173990.3:c.*21A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 VariationId is 257594.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 61 AR gene

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.*21A>G		3_prime_UTR	Exon 5 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.*21A>G		3_prime_UTR	Exon 5 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.*21A>G		3_prime_UTR	Exon 5 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.*21A>G		3_prime_UTR	Exon 5 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.*21A>G		3_prime_UTR	Exon 5 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.*21A>G		3_prime_UTR	Exon 5 of 5	ENSP00000381950.3	J3QT25

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

GnomAD2 exomes AF: 0.00500 AC: 1229 AN: 245600 AF XY: 0.00508

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 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

African (AFR) AF: 0.00117 AC: 39 AN: 33450

American (AMR) AF: 0.00259 AC: 115 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00175 AC: 150 AN: 85836

European-Finnish (FIN) AF: 0.00192 AC: 102 AN: 53188

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.00942 AC: 10448 AN: 1109612

Other (OTH) AF: 0.00596 AC: 359 AN: 60264

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

African (AFR) AF: 0.00154 AC: 64 AN: 41572

American (AMR) AF: 0.00451 AC: 69 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0100 AC: 682 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00701 Hom.: 0

Bravo AF: 0.00600

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.4
DANN	Benign	0.86
PhyloP100		-0.055
Mutation Taster		=100/0	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: rs111371929; hg19: chr11-61165769;