16-80976160-T-C

Variant names:

• chr16-80976160-T-C
• rs868158782
• NM_020188.5:c.173A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020188.5(CMC2):​c.173A>G​(p.Lys58Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,602,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CMC2 NM_020188.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12
• Publications: 0 publications found

Genes affected

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

ENSG00000286221 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1261867).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMC2	NM_020188.5	c.173A>G	p.Lys58Arg	missense_variant	Exon 4 of 4	ENST00000219400.8	NP_064573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMC2	ENST00000219400.8	c.173A>G	p.Lys58Arg	missense_variant	Exon 4 of 4	1	NM_020188.5	ENSP00000219400.3
ENSG00000286221	ENST00000650780.1	c.81+21154A>G		intron_variant	Intron 2 of 2			ENSP00000498782.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450244 Hom.: 0 Cov.: 26 AF XY: 0.00000138 AC XY: 1 AN XY: 722124

African (AFR) AF: 0.0000304 AC: 1 AN: 32880

American (AMR) AF: 0.00 AC: 0 AN: 43702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104060

Other (OTH) AF: 0.00 AC: 0 AN: 59974

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173A>G (p.K58R) alteration is located in exon 4 (coding exon 3) of the CMC2 gene. This alteration results from a A to G substitution at nucleotide position 173, causing the lysine (K) at amino acid position 58 to be replaced by an arginine (R). 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	0.062
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T;T;T;T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.64	.;.;.;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.79	N;N;N;N;N;N
REVEL	Benign	0.038
Sift	Benign	0.41	T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T;T
Polyphen		0.0060	B;B;B;B;.;.
Vest4		0.099
MutPred		0.52		Loss of ubiquitination at K58 (P = 0.0218);Loss of ubiquitination at K58 (P = 0.0218);Loss of ubiquitination at K58 (P = 0.0218);Loss of ubiquitination at K58 (P = 0.0218);.;.;
MVP		0.030
MPC		0.0065
ClinPred		0.28	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.041
gMVP		0.23
Mutation Taster		=49/151	disease causing

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

Other links and lift over

dbSNP: rs868158782; hg19: chr16-81010057;