16-66588094-C-T

Variant names:

• chr16-66588094-C-T
• rs931772089
• NM_144673.3:c.722C>T

Variant summary

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

The NM_144673.3(CMTM2):​c.722C>T​(p.Pro241Leu) 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. 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)
• Consequence: CMTM2 NM_144673.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.99

Genes affected

CMTM2 (HGNC:19173): (CKLF like MARVEL transmembrane domain containing 2) This gene belongs to the chemokine-like factor gene superfamily, a novel family that links the chemokine and the transmembrane 4 superfamilies of signaling molecules. The protein encoded by this gene may play an important role in testicular development. [provided by RefSeq, Jul 2008]

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=0.13089317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMTM2	NM_144673.3	c.722C>T	p.Pro241Leu	missense_variant	Exon 4 of 4	ENST00000268595.3	NP_653274.1
CMTM2	NM_001199317.2	c.563C>T	p.Pro188Leu	missense_variant	Exon 3 of 3		NP_001186246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMTM2	ENST00000268595.3	c.722C>T	p.Pro241Leu	missense_variant	Exon 4 of 4	1	NM_144673.3	ENSP00000268595.2
CMTM2	ENST00000379486.6	c.563C>T	p.Pro188Leu	missense_variant	Exon 3 of 3	1		ENSP00000368800.2
CMTM2	ENST00000532362.1	n.366C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2
CMTM2	ENST00000569316.1	n.*259C>T		downstream_gene_variant		5		ENSP00000454319.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.722C>T (p.P241L) alteration is located in exon 4 (coding exon 4) of the CMTM2 gene. This alteration results from a C to T substitution at nucleotide position 722, causing the proline (P) at amino acid position 241 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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.5
DANN	Benign	0.43
DEOGEN2	Benign	0.0056	.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.076
Sift	Uncertain	0.017	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.78	.;P
Vest4		0.22
MutPred		0.21		.;Gain of MoRF binding (P = 0.0199);
MVP		0.51
MPC		0.21
ClinPred		0.20	T
GERP RS		-4.6
Varity_R		0.039
gMVP		0.14

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: rs931772089; hg19: chr16-66621997;