4-46735002-T-G

Variant names:

• chr4-46735002-T-G
• rs1450941342
• NM_130902.3:c.191A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130902.3(COX7B2):​c.191A>C​(p.Glu64Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COX7B2 NM_130902.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0340

Genes affected

COX7B2 (HGNC:24381): (cytochrome c oxidase subunit 7B2) Predicted to enable cytochrome-c oxidase activity. Predicted to be involved in electron transport chain; oxidative phosphorylation; and proton transmembrane transport. Predicted to be located in mitochondrial respirasome. Predicted to be integral component of membrane. Predicted to be part of respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18658325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX7B2	NM_130902.3	c.191A>C	p.Glu64Ala	missense_variant	Exon 3 of 3	ENST00000355591.8	NP_570972.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX7B2	ENST00000355591.8	c.191A>C	p.Glu64Ala	missense_variant	Exon 3 of 3	1	NM_130902.3	ENSP00000347799.3
COX7B2	ENST00000396533.5	c.191A>C	p.Glu64Ala	missense_variant	Exon 4 of 4	1		ENSP00000379784.1
COX7B2	ENST00000543208.5	c.188A>C	p.Glu63Ala	missense_variant	Exon 3 of 3	5		ENSP00000437439.1
COX7B2	ENST00000505102.1	c.*93A>C		downstream_gene_variant		3		ENSP00000423519.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191A>C (p.E64A) alteration is located in exon 3 (coding exon 1) of the COX7B2 gene. This alteration results from a A to C substitution at nucleotide position 191, causing the glutamic acid (E) at amino acid position 64 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	11
DANN	Benign	0.88
DEOGEN2	Benign	0.085	T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.049
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.22	T;T;T
Polyphen		0.24	B;B;.
Vest4		0.30
MutPred		0.65		Gain of MoRF binding (P = 0.0612);Gain of MoRF binding (P = 0.0612);.;
MVP		0.061
MPC		0.0011
ClinPred		0.19	T
GERP RS		0.65
Varity_R		0.080
gMVP		0.21

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

LitVar

Other links and lift over

dbSNP: rs1450941342; hg19: chr4-46737019;