Genetic Variant CMC2:p.His10Asp (chr16-80997367-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020188.5(CMC2):c.28C>G(p.His10Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000152 in 1,583,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CMC2
NM_020188.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.09

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMC2	NM_020188.5 link	c.28C>G	p.His10Asp	missense_variant	Exon 2 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.28C>G	p.His10Asp	missense_variant	Exon 2 of 4	1	NM_020188.5	ENSP00000219400.3		Q9NRP2
ENSG00000286221	ENST00000650780.1 link	c.28C>G	p.His10Asp	missense_variant	Exon 2 of 3			ENSP00000498782.1		A0A494C0Z3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151588

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251258

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000154

AC:

AN:

1431704

Hom.:

Cov.:

AF XY:

0.00000842

AC XY:

AN XY:

712470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32366

American (AMR)

AF:

0.00

AC:

AN:

43792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24814

East Asian (EAS)

AF:

0.00

AC:

AN:

38006

South Asian (SAS)

AF:

0.00

AC:

AN:

85966

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.0000192

AC:

AN:

1092266

Other (OTH)

AF:

0.0000172

AC:

AN:

58160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151588

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41334

American (AMR)

AF:

0.00

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5086

South Asian (SAS)

AF:

0.00

AC:

AN:

4694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67926

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.28C>G (p.H10D) alteration is located in exon 2 (coding exon 1) of the CMC2 gene. This alteration results from a C to G substitution at nucleotide position 28, causing the histidine (H) at amino acid position 10 to be replaced by an aspartic acid (D). 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

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;T;.;D;D;D;.;D;D;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

.;.;T;.;.;D;.;.;D;D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.57

PhyloP100

6.1

PrimateAI

Uncertain

0.79

PROVEAN

Pathogenic

-7.3

D;D;D;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0080

D;D;D;D;D;D;D;D;D;D;.

Sift4G

Uncertain

0.017

D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;.;D;D;D;.;.;.;.;.

Vest4

0.88

MutPred

0.62

Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);

MVP

0.27

MPC

0.022

ClinPred

0.98

GERP RS

6.0

Varity_R

0.95

gMVP

0.86

Mutation Taster

=25/175

disease causing

(source)

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

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16-80997367-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over