rs2072234758

Variant names:

• chr12-111937166-C-G
• rs2072234758
• NM_001193531.2:c.443G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193531.2(TMEM116):​c.443G>C​(p.Ser148Thr) 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. 14/17 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: TMEM116 NM_001193531.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.184
• Publications: 0 publications found

Genes affected

TMEM116 (HGNC:25084): (transmembrane protein 116) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1643613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM116	NM_001193531.2	c.443G>C	p.Ser148Thr	missense_variant	Exon 7 of 11	ENST00000552374.7	NP_001180460.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM116	ENST00000552374.7	c.443G>C	p.Ser148Thr	missense_variant	Exon 7 of 11	1	NM_001193531.2	ENSP00000447731.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.443G>C (p.S148T) alteration is located in exon 7 (coding exon 6) of the TMEM116 gene. This alteration results from a G to C substitution at nucleotide position 443, causing the serine (S) at amino acid position 148 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.7
DANN	Benign	0.18
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.18
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.081
Sift	Benign	0.54	T
Polyphen		1.0	D
Vest4		0.36
MutPred		0.18		Gain of catalytic residue at P3 (P = 0.0408);
MVP		0.030
ClinPred		0.15	T
GERP RS		-0.15
Varity_R		0.045
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs2072234758; hg19: chr12-112374970;