11-61397949-G-C

Position:

• chr11-61397949-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001173990.3(TMEM216):​c.405G>C​(p.Glu135Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain Transmembrane protein 216 (size 144) in uniprot entity TM216_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_001173990.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1558742).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.405G>C	p.Glu135Asp	missense_variant	4/5	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.405G>C	p.Glu135Asp	missense_variant	4/5		NP_001167462.1
TMEM216	NM_016499.6	c.222G>C	p.Glu74Asp	missense_variant	4/5		NP_057583.2
TMEM216	NM_001330285.2	c.222G>C	p.Glu74Asp	missense_variant	4/5		NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000515837.7	c.405G>C	p.Glu135Asp	missense_variant	4/5	2	NM_001173990.3	ENSP00000440638.1
TMEM216	ENST00000334888.10	c.405G>C	p.Glu135Asp	missense_variant	4/5	2		ENSP00000334844.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461574 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 727088

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	0.0076	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.84	L;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.61	T;T;T
Vest4		0.16
MVP		0.40
MPC		0.13
ClinPred		0.33	T
GERP RS		2.1
Varity_R		0.15
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs748486939; hg19: chr11-61165421;