chr2-677342-G-C

Position:

• chr2-677342-G-C

Variant summary

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

The NM_152834.4(TMEM18):​c.4C>G​(p.Pro2Ala) 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. 13/19 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)
• Consequence: TMEM18 NM_152834.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.543

Genes affected

TMEM18 (HGNC:25257): (transmembrane protein 18) Predicted to enable DNA binding activity. Involved in cell migration. Located in nuclear membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM18-DT (HGNC:54481): (TMEM18 divergent transcript)

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=0.14582345).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM18	NM_152834.4	c.4C>G	p.Pro2Ala	missense_variant	1/5	ENST00000281017.8	NP_690047.2
TMEM18	NM_001352680.2	c.-517C>G		5_prime_UTR_variant	1/6		NP_001339609.1
TMEM18-DT	NR_183417.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM18	ENST00000281017.8	c.4C>G	p.Pro2Ala	missense_variant	1/5	1	NM_152834.4	ENSP00000281017	P1
TMEM18-DT	ENST00000445418.1	n.157G>C		non_coding_transcript_exon_variant	1/3	2
TMEM18	ENST00000432667.5	c.4C>G	p.Pro2Ala	missense_variant, NMD_transcript_variant	1/6	5		ENSP00000390474

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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 20, 2021

The c.4C>G (p.P2A) alteration is located in exon 1 (coding exon 1) of the TMEM18 gene. This alteration results from a C to G substitution at nucleotide position 4, causing the proline (P) at amino acid position 2 to be replaced by an alanine (A). 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	0.13
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.018
Sift	Benign	0.14	T
Sift4G	Benign	0.073	T
Polyphen		0.0080	B
Vest4		0.35
MutPred		0.17		Gain of sheet (P = 0.0344);
MVP		0.014
MPC		0.14
ClinPred		0.10	T
GERP RS		0.55
Varity_R		0.038

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: rs113705272; hg19: chr2-677342;