4-46735000-A-G

Position:

• chr4-46735000-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_130902.3(COX7B2):​c.193T>C​(p.Trp65Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.29

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX7B2	NM_130902.3	c.193T>C	p.Trp65Arg	missense_variant	3/3	ENST00000355591.8	NP_570972.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX7B2	ENST00000355591.8	c.193T>C	p.Trp65Arg	missense_variant	3/3	1	NM_130902.3	ENSP00000347799.3
COX7B2	ENST00000396533.5	c.193T>C	p.Trp65Arg	missense_variant	4/4	1		ENSP00000379784.1
COX7B2	ENST00000543208.5	c.190T>C	p.Trp64Arg	missense_variant	3/3	5		ENSP00000437439.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.193T>C (p.W65R) alteration is located in exon 3 (coding exon 1) of the COX7B2 gene. This alteration results from a T to C substitution at nucleotide position 193, causing the tryptophan (W) at amino acid position 65 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	-0.024	T
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-12	D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.090	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.84
MutPred		0.92		Gain of disorder (P = 0.039);Gain of disorder (P = 0.039);.;
MVP		0.40
MPC		0.00061
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.53
gMVP		0.51

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: rs1714271082; hg19: chr4-46737017;