16-80976168-G-C

Variant names:

• chr16-80976168-G-C
• rs140972336
• NM_020188.5:c.165C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_020188.5(CMC2):​c.165C>G​(p.Asn55Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000666 in 1,591,270 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (1 hom.)
• Consequence: CMC2 NM_020188.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02586031).
• BP6: Variant 16-80976168-G-C is Benign according to our data. Variant chr16-80976168-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2511777.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CMC2	NM_020188.5	c.165C>G	p.Asn55Lys	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.165C>G	p.Asn55Lys	missense_variant	Exon 4 of 4	1	NM_020188.5	ENSP00000219400.3
ENSG00000286221	ENST00000650780.1	c.81+21146C>G		intron_variant	Intron 2 of 2			ENSP00000498782.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000867

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000412 AC: 101 AN: 244952 AF XY: 0.000384

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000903

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000843

Gnomad OTH exome AF: 0.000338

GnomAD4 exome AF: 0.000691 AC: 994 AN: 1439082 Hom.: 1 Cov.: 25 AF XY: 0.000665 AC XY: 477 AN XY: 717072

African (AFR) AF: 0.0000923 AC: 3 AN: 32498

American (AMR) AF: 0.000115 AC: 5 AN: 43336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25806

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.00 AC: 0 AN: 84822

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.000883 AC: 967 AN: 1094972

Other (OTH) AF: 0.000286 AC: 17 AN: 59538

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27 AN XY: 74414

African (AFR) AF: 0.0000963 AC: 4 AN: 41520

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000867 AC: 59 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000630 Hom.: 0

Bravo AF: 0.000502

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000546

EpiControl AF: 0.000654

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 06, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.6
DANN	Benign	0.17
DEOGEN2	Benign	0.15	T;T;T;T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.57	.;.;.;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.026	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.1	N;N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	1.0	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.025
MutPred		0.38		Gain of methylation at N55 (P = 0.0087);Gain of methylation at N55 (P = 0.0087);Gain of methylation at N55 (P = 0.0087);Gain of methylation at N55 (P = 0.0087);.;.;
MVP		0.030
MPC		0.0053
ClinPred		0.0084	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.17
Mutation Taster		=30/170	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: rs140972336; hg19: chr16-81010065;