Genetic Variant CMC2:p.Ser59Cys (chr16-80976158-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020188.5(CMC2):c.175A>T(p.Ser59Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,452,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CMC2
NM_020188.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.00

Publications

0 publications found

Variant links:

Genes affected

CMC2 (HGNC:24447): (C-X9-C motif containing 2) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

CMC2 links:

ENSG00000286221 (HGNC:):

ENSG00000286221 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38758862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMC2	NM_020188.5 link	c.175A>T	p.Ser59Cys	missense_variant	Exon 4 of 4	ENST00000219400.8	NP_064573.1	Q9NRP2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMC2	ENST00000219400.8 link	c.175A>T	p.Ser59Cys	missense_variant	Exon 4 of 4	1	NM_020188.5	ENSP00000219400.3		Q9NRP2
ENSG00000286221	ENST00000650780.1 link	c.81+21156A>T		intron_variant	Intron 2 of 2			ENSP00000498782.1		A0A494C0Z3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452454

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

723112

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33018

American (AMR)

AF:

0.0000454

AC:

AN:

44076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.00

AC:

AN:

85572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53106

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105262

Other (OTH)

AF:

0.00

AC:

AN:

60072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 17, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.175A>T (p.S59C) alteration is located in exon 4 (coding exon 3) of the CMC2 gene. This alteration results from a A to T substitution at nucleotide position 175, causing the serine (S) at amino acid position 59 to be replaced by a cysteine (C). 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

Uncertain

0.50

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;T;T;T;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.75

.;.;.;T;.;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.39

T;T;T;T;T;T

MetaSVM

Benign

-0.61

PhyloP100

4.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.1

D;D;D;D;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.0050

D;D;D;D;T;T

Sift4G

Uncertain

0.0080

D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;.

Vest4

0.33

MutPred

0.58

Loss of phosphorylation at S59 (P = 0.0062);Loss of phosphorylation at S59 (P = 0.0062);Loss of phosphorylation at S59 (P = 0.0062);Loss of phosphorylation at S59 (P = 0.0062);.;.;

MVP

0.39

MPC

0.027

ClinPred

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over