15-76137769-C-G

Position:

• chr15-76137769-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000388942.8(TMEM266):​c.101C>G​(p.Thr34Ser) 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM266 ENST00000388942.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

Genes affected

TMEM266 (HGNC:26763): (transmembrane protein 266) Enables protein homodimerization activity. Predicted to be involved in transmembrane transport. Located in cytosol; dendrite; and plasma membrane. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.119494826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM266	NM_152335.5	c.77C>G	p.Thr26Ser	missense_variant	3/11		NP_689548.3
TMEM266	XM_017021915.2	c.101C>G	p.Thr34Ser	missense_variant	5/13		XP_016877404.1
TMEM266	XM_047432151.1	c.101C>G	p.Thr34Ser	missense_variant	5/13		XP_047288107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM266	ENST00000388942.8	c.101C>G	p.Thr34Ser	missense_variant	3/11	5	NM_152335.3	ENSP00000373594.4
TMEM266	ENST00000561302.5	n.101C>G		non_coding_transcript_exon_variant	3/11	1		ENSP00000453957.2
TMEM266	ENST00000484722.5	n.101C>G		non_coding_transcript_exon_variant	3/11	5		ENSP00000435049.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2024

The c.101C>G (p.T34S) alteration is located in exon 3 (coding exon 2) of the TMEM266 gene. This alteration results from a C to G substitution at nucleotide position 101, causing the threonine (T) at amino acid position 34 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0032	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.028
Sift	Benign	0.18	T
Sift4G	Benign	0.42	T
Polyphen		0.14	B
Vest4		0.22
MutPred		0.21		Gain of disorder (P = 0.0546);
MVP		0.28
MPC		0.21
ClinPred		0.30	T
GERP RS		3.1
Varity_R		0.047
gMVP		0.23

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: rs1486216365; hg19: chr15-76430110;