X-100650862-C-T

Variant names:

• chrX-100650862-C-T
• rs772122754
• NM_014467.3:c.160C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014467.3(SRPX2):​c.160C>T​(p.Arg54*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,918 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R54R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SRPX2 NM_014467.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.260
• Publications: 0 publications found

Genes affected

SRPX2 (HGNC:30668): (sushi repeat containing protein X-linked 2) This gene encodes a secreted protein that contains three sushi repeat motifs. The encoded protein may play a role in the development of speech and language centers in the brain. This protein may also be involved in angiogenesis. Mutations in this gene are the cause of bilateral perisylvian polymicrogyria, rolandic epilepsy, speech dyspraxia and cognitive disability. [provided by RefSeq, May 2010]

SRPX2 Gene-Disease associations (from GenCC):

• rolandic epilepsy-speech dyspraxia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• polymicrogyria, bilateral perisylvian, X-linked

  Inheritance: XL Classification: LIMITED Submitted by: G2P
• rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked

  Inheritance: XL Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014467.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRPX2	NM_014467.3	MANE Select	c.160C>T	p.Arg54*	stop_gained	Exon 3 of 11	NP_055282.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRPX2	ENST00000373004.5	TSL:1 MANE Select	c.160C>T	p.Arg54*	stop_gained	Exon 3 of 11	ENSP00000362095.3
	SRPX2	ENST00000638458.1	TSL:5	c.160C>T	p.Arg54*	stop_gained	Exon 2 of 7	ENSP00000492168.1
	SRPX2	ENST00000640889.1	TSL:5	c.160C>T	p.Arg54*	stop_gained	Exon 3 of 7	ENSP00000492571.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111415 Hom.: 0 Cov.: 23

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 182650 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091918 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 357456

African (AFR) AF: 0.00 AC: 0 AN: 26253

American (AMR) AF: 0.00 AC: 0 AN: 35191

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19341

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40367

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4091

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836682

Other (OTH) AF: 0.00 AC: 0 AN: 45895

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 111415 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33587

African (AFR) AF: 0.00 AC: 0 AN: 30634

American (AMR) AF: 0.00 AC: 0 AN: 10514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3501

South Asian (SAS) AF: 0.00 AC: 0 AN: 2588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6021

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53082

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	34
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.33	N
PhyloP100		0.26
Vest4		0.67
GERP RS		-7.2
Mutation Taster		=40/160	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs772122754; hg19: chrX-99905859; COSMIC: COSV65934443; COSMIC: COSV65934443;