16-66579864-G-A

Variant names:

• chr16-66579864-G-A
• rs146637368
• NM_144673.3:c.257G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_144673.3(CMTM2):​c.257G>A​(p.Gly86Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G86V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CMTM2 NM_144673.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71
• Publications: 0 publications found

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]

ENSG00000260650 (HGNC:58533):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144673.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMTM2	NM_144673.3	MANE Select	c.257G>A	p.Gly86Glu	missense	Exon 1 of 4	NP_653274.1	Q8TAZ6-1
	CMTM2	NM_001199317.2		c.257G>A	p.Gly86Glu	missense	Exon 1 of 3	NP_001186246.1	Q8TAZ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMTM2	ENST00000268595.3	TSL:1 MANE Select	c.257G>A	p.Gly86Glu	missense	Exon 1 of 4	ENSP00000268595.2	Q8TAZ6-1
	CMTM2	ENST00000379486.6	TSL:1	c.257G>A	p.Gly86Glu	missense	Exon 1 of 3	ENSP00000368800.2	Q8TAZ6-2
	CMTM2	ENST00000569316.1	TSL:5	n.91+166G>A		intron	N/A	ENSP00000454319.1	H3BMC0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461704 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.015	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.81		Loss of MoRF binding (P = 0.0585)
MVP		0.52
MPC		0.90
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.026	Neutral
Varity_R		0.74
gMVP		0.37
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146637368; hg19: chr16-66613767;