chrX-21856893-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_206923.4(YY2):​c.409C>T​(p.Arg137Cys) 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: 23)

Consequence

YY2
NM_206923.4 missense

Scores

2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.324
Variant links:
Genes affected
YY2 (HGNC:31684): (YY2 transcription factor) The protein encoded by this gene is a transcription factor that includes several Kruppel-like zinc fingers in its C-terminal region. It possesses both activation and repression domains, and it can therefore have both positive and negative effects on the transcription of target genes. This gene has an intronless coding region, and it appears to have arisen by retrotransposition of the related YY1 transcription factor gene, which is located on chromosome 14. [provided by RefSeq, May 2010]
MBTPS2 (HGNC:15455): (membrane bound transcription factor peptidase, site 2) This gene encodes a intramembrane zinc metalloprotease, which is essential in development. This protease functions in the signal protein activation involved in sterol control of transcription and the ER stress response. Mutations in this gene have been associated with ichthyosis follicularis with atrichia and photophobia (IFAP syndrome); IFAP syndrome has been quantitatively linked to a reduction in cholesterol homeostasis and ER stress response.[provided by RefSeq, Aug 2009]

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ACMG classification

Classification made for transcript

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=0.10705465).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
YY2NM_206923.4 linkc.409C>T p.Arg137Cys missense_variant Exon 1 of 1 ENST00000429584.3 NP_996806.2 O15391
MBTPS2NM_015884.4 linkc.670+3390C>T intron_variant Intron 5 of 10 ENST00000379484.10 NP_056968.1 O43462

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
YY2ENST00000429584.3 linkc.409C>T p.Arg137Cys missense_variant Exon 1 of 1 6 NM_206923.4 ENSP00000389381.2 O15391
MBTPS2ENST00000379484.10 linkc.670+3390C>T intron_variant Intron 5 of 10 1 NM_015884.4 ENSP00000368798.5 O43462
MBTPS2ENST00000365779.2 linkc.670+3390C>T intron_variant Intron 5 of 6 1 ENSP00000368796.1 B9ZVQ3
MBTPS2ENST00000465888.1 linkn.1162C>T non_coding_transcript_exon_variant Exon 6 of 6 2

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.409C>T (p.R137C) alteration is located in exon 1 (coding exon 1) of the YY2 gene. This alteration results from a C to T substitution at nucleotide position 409, causing the arginine (R) at amino acid position 137 to be replaced by a cysteine (C). 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
0.31
BayesDel_addAF
Benign
-0.42
T
BayesDel_noAF
Benign
-0.84
CADD
Benign
2.9
DANN
Benign
0.96
DEOGEN2
Benign
0.070
T
FATHMM_MKL
Benign
0.0069
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.0034
T
MetaRNN
Benign
0.11
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.6
L
PrimateAI
Benign
0.21
T
PROVEAN
Uncertain
-2.6
D
REVEL
Benign
0.063
Sift
Benign
0.045
D
Sift4G
Uncertain
0.047
D
Polyphen
0.96
D
Vest4
0.051
MutPred
0.30
Loss of MoRF binding (P = 0.0073);
MVP
0.13
MPC
1.3
ClinPred
0.93
D
GERP RS
-2.0
Varity_R
0.11
gMVP
0.089

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21875011; API