rs10897158

Variant names:

• chr11-61398269-G-A
• rs10897158
• ENST00000334888.10:c.440G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61398269-G-A
• chr11-61398269-G-C
• chr11-61398269-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The ENST00000334888.10(TMEM216):​c.440G>A​(p.Arg147Lys) 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 benign 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. R147M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM216 ENST00000334888.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.817
• Publications: 42 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):

• 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM216	NM_001173990.3	c.432-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 4	ENST00000515837.7	NP_001167461.1
TMEM216	NM_001173991.3	c.440G>A	p.Arg147Lys	missense_variant	Exon 5 of 5		NP_001167462.1
TMEM216	NM_016499.6	c.257G>A	p.Arg86Lys	missense_variant	Exon 5 of 5		NP_057583.2
TMEM216	NM_001330285.2	c.249-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 4		NP_001317214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM216	ENST00000334888.10	c.440G>A	p.Arg147Lys	missense_variant	Exon 5 of 5	2		ENSP00000334844.5
TMEM216	ENST00000515837.7	c.432-1G>A		splice_acceptor_variant, intron_variant	Intron 4 of 4	2	NM_001173990.3	ENSP00000440638.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1458988 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 725646

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 85968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110272

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.029	D
PhyloP100		0.82
ClinPred		0.57	D
GERP RS		4.1
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.80		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.39		Position offset: 2
DS_AL_spliceai		0.80		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10897158; hg19: chr11-61165741;