2-191956313-C-T

Variant names:

• chr2-191956313-C-T
• rs1342749759
• NM_016192.4:c.811G>A

Variant summary

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

The NM_016192.4(TMEFF2):​c.811G>A​(p.Gly271Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEFF2 NM_016192.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89

Genes affected

TMEFF2 (HGNC:11867): (transmembrane protein with EGF like and two follistatin like domains 2) This gene encodes a member of the tomoregulin family of transmembrane proteins. This protein has been shown to function as both an oncogene and a tumor suppressor depending on the cellular context and may regulate prostate cancer cell invasion. Multiple soluble forms of this protein have been identified that arise from both an alternative splice variant and ectodomain shedding. Additionally, this gene has been found to be hypermethylated in multiple cancer types. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2015]

CAVIN2-AS1 (HGNC:40517): (CAVIN2 and TMEFF2 antisense RNA 1)

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=0.20513844).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEFF2	NM_016192.4	c.811G>A	p.Gly271Ser	missense_variant	Exon 8 of 10	ENST00000272771.10	NP_057276.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEFF2	ENST00000272771.10	c.811G>A	p.Gly271Ser	missense_variant	Exon 8 of 10	1	NM_016192.4	ENSP00000272771.5
TMEFF2	ENST00000392314.5	c.811G>A	p.Gly271Ser	missense_variant	Exon 8 of 10	1		ENSP00000376128.1
CAVIN2-AS1	ENST00000424116.7	n.239-78381C>T		intron_variant	Intron 1 of 2	2
CAVIN2-AS1	ENST00000428980.6	n.499+33269C>T		intron_variant	Intron 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.811G>A (p.G271S) alteration is located in exon 8 (coding exon 8) of the TMEFF2 gene. This alteration results from a G to A substitution at nucleotide position 811, causing the glycine (G) at amino acid position 271 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	0.067
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.0028
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.070
Sift	Benign	0.037	D;D
Sift4G	Benign	0.30	T;T
Polyphen		0.059	.;B
Vest4		0.32
MutPred		0.64		Gain of disorder (P = 0.0971);Gain of disorder (P = 0.0971);
MVP		0.53
MPC		0.77
ClinPred		0.82	D
GERP RS		4.5
Varity_R		0.17
gMVP		0.55

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: rs1342749759; hg19: chr2-192821039; COSMIC: COSV55833927;