Genetic Variant CXorf66:p.Cys266Tyr (chrX-139956185-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001013403.3(CXorf66):c.797G>A(p.Cys266Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,209,716 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 6 hem. )

Consequence

CXorf66
NM_001013403.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.433

Variant links:

Genes affected

CXorf66 (HGNC:33743): (chromosome X open reading frame 66) The protein encoded by this gene is predicted to be a type I membrane protein, however, its exact function is not known. [provided by RefSeq, Sep 2009]

CXorf66 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CXorf66	NM_001013403.3 link	c.797G>A	p.Cys266Tyr	missense_variant	Exon 3 of 3	ENST00000370540.2	NP_001013421.1	Q5JRM2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CXorf66	ENST00000370540.2 link	c.797G>A	p.Cys266Tyr	missense_variant	Exon 3 of 3	1	NM_001013403.3	ENSP00000359571.1		Q5JRM2

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112011

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34177

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:

0.0000563

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1097705

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363063

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000166

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112011

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34177

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000563

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000611

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.797G>A (p.C266Y) alteration is located in exon 3 (coding exon 3) of the CXorf66 gene. This alteration results from a G to A substitution at nucleotide position 797, causing the cysteine (C) at amino acid position 266 to be replaced by a tyrosine (Y). 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

0.17

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.12

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.44

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

PROVEAN

Pathogenic

-8.0

REVEL

Benign

0.10

Sift

Uncertain

0.015

Sift4G

Benign

0.28

Polyphen

1.0

Vest4

0.54

MVP

0.088

MPC

0.54

ClinPred

0.91

GERP RS

3.3

Varity_R

0.54

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over