2-96254834-C-G

Variant names:

• chr2-96254834-C-G
• rs143522428
• NM_017849.4:c.408G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_017849.4(TMEM127):​c.408G>C​(p.Thr136Thr) variant causes a splice region, synonymous 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T136T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM127 NM_017849.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00006172
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.972
• Publications: 0 publications found

Genes affected

TMEM127 (HGNC:26038): (transmembrane protein 127) This gene encodes a transmembrane protein with four predicted transmembrane domains. The protein is associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, and may participate in protein trafficking between these structures. Mutations in this gene and several other genes cause pheochromocytomas. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2022]

TMEM127 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• renal cell carcinoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-96254834-C-G is Benign according to our data. Variant chr2-96254834-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1003308.
• BP7: Synonymous conserved (PhyloP=0.972 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017849.4. 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
	TMEM127	NM_017849.4	MANE Select	c.408G>C	p.Thr136Thr	splice_region synonymous	Exon 3 of 4	NP_060319.1	O75204
	TMEM127	NM_001193304.3		c.408G>C	p.Thr136Thr	splice_region synonymous	Exon 3 of 4	NP_001180233.1	O75204
	TMEM127	NM_001407282.1		c.156G>C	p.Thr52Thr	splice_region synonymous	Exon 2 of 3	NP_001394211.1	C9J4H2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM127	ENST00000258439.8	TSL:1 MANE Select	c.408G>C	p.Thr136Thr	splice_region synonymous	Exon 3 of 4	ENSP00000258439.3	O75204
	TMEM127	ENST00000432959.2	TSL:1	c.408G>C	p.Thr136Thr	splice_region synonymous	Exon 3 of 4	ENSP00000416660.1	O75204
	TMEM127	ENST00000910913.1		c.408G>C	p.Thr136Thr	splice_region synonymous	Exon 2 of 3	ENSP00000580972.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary pheochromocytoma-paraganglioma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.51
DANN	Benign	0.63
PhyloP100		0.97
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000062
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs143522428; hg19: chr2-96920572;