12-125350145-C-T

Position:

• chr12-125350145-C-T

Variant summary

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

The NM_001366854.1(TMEM132B):​c.761C>T​(p.Pro254Leu) 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 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMEM132B NM_001366854.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

Genes affected

TMEM132B (HGNC:29397): (transmembrane protein 132B) Predicted to be integral component of 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=0.07080755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM132B	NM_001366854.1	c.761C>T	p.Pro254Leu	missense_variant	2/9	ENST00000682704.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM132B	ENST00000682704.1	c.761C>T	p.Pro254Leu	missense_variant	2/9		NM_001366854.1	P2
TMEM132B	ENST00000299308.7	c.746C>T	p.Pro249Leu	missense_variant	2/9	5		A2
TMEM132B	ENST00000534945.2	n.694C>T		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 26, 2023

The c.746C>T (p.P249L) alteration is located in exon 2 (coding exon 2) of the TMEM132B gene. This alteration results from a C to T substitution at nucleotide position 746, causing the proline (P) at amino acid position 249 to be replaced by a leucine (L). 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	0.069
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.21
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.95	D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.079
Sift	Benign	0.38	T
Sift4G	Benign	0.66	T
Polyphen		0.0010	B
Vest4		0.13
MutPred		0.43		Gain of catalytic residue at L246 (P = 0.0213);
MVP		0.061
MPC		0.26
ClinPred		0.023	T
GERP RS		4.5
Varity_R		0.016
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-125834691; COSMIC: COSV54773261; COSMIC: COSV54773261;