rs1554972406

Variant names:

• chr11-61392633-T-A
• rs1554972406
• NM_001173990.3:c.2T>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61392633-T-A
• chr11-61392633-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001173990.3(TMEM216):​c.2T>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000977 in 1,535,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.436
• 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, 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: Uncertain_significance. The variant received 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 61392653. Lost 0.050 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.2T>A	p.Met1?	start_lost	Exon 1 of 5	NP_001167461.1	Q9P0N5-1
	TMEM216	NM_001173991.3		c.2T>A	p.Met1?	start_lost	Exon 1 of 5	NP_001167462.1	Q9P0N5-3
	TMEM216	NM_016499.6		c.-196T>A		5_prime_UTR	Exon 1 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.2T>A	p.Met1?	start_lost	Exon 1 of 5	ENSP00000440638.1	Q9P0N5-1
	TMEM216	ENST00000334888.10	TSL:2	c.2T>A	p.Met1?	start_lost	Exon 1 of 5	ENSP00000334844.5	Q9P0N5-3
	TMEM216	ENST00000398979.7	TSL:1	c.-196T>A		5_prime_UTR	Exon 1 of 5	ENSP00000381950.3	J3QT25

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.0000101 AC: 14 AN: 1383054 Hom.: 0 Cov.: 32 AF XY: 0.00000879 AC XY: 6 AN XY: 682520

African (AFR) AF: 0.0000633 AC: 2 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078266

Other (OTH) AF: 0.00 AC: 0 AN: 57878

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

African (AFR) AF: 0.0000241 AC: 1 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Joubert syndrome (1)
-	1	-	Joubert syndrome 2;C1864148:Meckel syndrome, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.055	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.37	T
PhyloP100		-0.44
PROVEAN	Benign	0.010	N
REVEL	Benign	0.20
Sift	Benign	0.090	T
Sift4G	Benign	1.0	T
Vest4		0.15
MutPred		0.86		Gain of glycosylation at M1 (P = 0.0303)
MVP		0.26
ClinPred		0.071	T
GERP RS		-2.1
PromoterAI		0.053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.24
gMVP		0.58
Mutation Taster		=107/93	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554972406; hg19: chr11-61160105;