X-21857235-C-T

Variant names:

• chrX-21857235-C-T
• NM_206923.4:c.751C>T

Variant summary

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

The NM_206923.4(YY2):​c.751C>T​(p.Pro251Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: YY2 NM_206923.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.144

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]

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=0.21486908).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
YY2	NM_206923.4	c.751C>T	p.Pro251Ser	missense_variant	Exon 1 of 1	ENST00000429584.3	NP_996806.2
MBTPS2	NM_015884.4	c.670+3732C>T		intron_variant	Intron 5 of 10	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
YY2	ENST00000429584.3	c.751C>T	p.Pro251Ser	missense_variant	Exon 1 of 1	6	NM_206923.4	ENSP00000389381.2
MBTPS2	ENST00000379484.10	c.670+3732C>T		intron_variant	Intron 5 of 10	1	NM_015884.4	ENSP00000368798.5
MBTPS2	ENST00000365779.2	c.670+3732C>T		intron_variant	Intron 5 of 6	1		ENSP00000368796.1
MBTPS2	ENST00000465888.1	n.1504C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1098097 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363479

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751C>T (p.P251S) 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 751, causing the proline (P) at amino acid position 251 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.092
Sift	Benign	0.12	T
Sift4G	Benign	0.35	T
Polyphen		0.98	D
Vest4		0.088
MutPred		0.29		Loss of loop (P = 0.0112);
MVP		0.099
MPC		0.79
ClinPred		0.56	D
GERP RS		1.6
Varity_R		0.14
gMVP		0.27

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-21875353;