11-61397797-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001173990.3(TMEM216):c.253C>G(p.Arg85Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMEM216 NM_001173990.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a chain Transmembrane protein 216 (size 144) in uniprot entity TM216_HUMAN there are 12 pathogenic changes around while only 4 benign (75%) in NM_001173990.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM216	NM_001173990.3	c.253C>G	p.Arg85Gly	missense_variant	4/5	ENST00000515837.7
TMEM216	NM_001173991.3	c.253C>G	p.Arg85Gly	missense_variant	4/5
TMEM216	NM_016499.6	c.70C>G	p.Arg24Gly	missense_variant	4/5
TMEM216	NM_001330285.2	c.70C>G	p.Arg24Gly	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM216	ENST00000515837.7	c.253C>G	p.Arg85Gly	missense_variant	4/5	2	NM_001173990.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248910 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134992

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.60
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.16	T;T;T
Vest4		0.66
MVP		0.74
MPC		0.65
ClinPred		0.94	D
GERP RS		2.7
Varity_R		0.63
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs11230683; hg19: chr11-61165269;