2-96253874-G-C

Variant summary

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

The NM_017849.4(TMEM127):c.651C>G(p.Asn217Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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. Synonymous variant affecting the same amino acid position (i.e. N217N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM127 NM_017849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175

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]

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=0.10246906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM127	NM_017849.4	c.651C>G	p.Asn217Lys	missense_variant	4/4	ENST00000258439.8
TMEM127	NM_001193304.3	c.651C>G	p.Asn217Lys	missense_variant	4/4
TMEM127	NM_001407282.1	c.399C>G	p.Asn133Lys	missense_variant	3/3
TMEM127	NM_001407283.1	c.399C>G	p.Asn133Lys	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM127	ENST00000258439.8	c.651C>G	p.Asn217Lys	missense_variant	4/4	1	NM_017849.4	P1
TMEM127	ENST00000432959.1	c.651C>G	p.Asn217Lys	missense_variant	4/4	1		P1
TMEM127	ENST00000435268.1	c.399C>G	p.Asn133Lys	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	0.027
Dann	Benign	0.89
DEOGEN2	Benign	0.016	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.80	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.081	B;B;.
Vest4		0.26
MutPred		0.19		Gain of ubiquitination at N217 (P = 9e-04);Gain of ubiquitination at N217 (P = 9e-04);.;
MVP		0.28
MPC		0.51
ClinPred		0.33	T
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.075
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-96919612;