rs5921620

Variant names:

• chrX-100664479-T-C
• rs5921620
• NM_014467.3:c.356-295T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_014467.3(SRPX2):​c.356-295T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 110,198 control chromosomes in the GnomAD database, including 3,950 homozygotes. There are 9,660 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.30 (3950 hom., 9660 hem., cov: 22)
• Consequence: SRPX2 NM_014467.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.308
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-100664479-T-C is Benign according to our data. Variant chrX-100664479-T-C is described in ClinVar as Benign. ClinVar VariationId is 668969.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3	c.356-295T>C		intron_variant	Intron 4 of 10	ENST00000373004.5	NP_055282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5	c.356-295T>C		intron_variant	Intron 4 of 10	1	NM_014467.3	ENSP00000362095.3

Frequencies

GnomAD3 genomes AF: 0.297 AC: 32658 AN: 110144 Hom.: 3939 Cov.: 22

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.291

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.293

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.297 AC: 32711 AN: 110198 Hom.: 3950 Cov.: 22 AF XY: 0.297 AC XY: 9660 AN XY: 32520

African (AFR) AF: 0.434 AC: 13126 AN: 30251

American (AMR) AF: 0.363 AC: 3756 AN: 10348

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 415 AN: 2631

East Asian (EAS) AF: 0.431 AC: 1492 AN: 3465

South Asian (SAS) AF: 0.474 AC: 1215 AN: 2564

European-Finnish (FIN) AF: 0.291 AC: 1667 AN: 5721

Middle Eastern (MID) AF: 0.174 AC: 37 AN: 213

European-Non Finnish (NFE) AF: 0.195 AC: 10321 AN: 52821

Other (OTH) AF: 0.299 AC: 452 AN: 1514

Alfa AF: 0.241 Hom.: 19077

Bravo AF: 0.313

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	7.8
DANN	Benign	0.67
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs5921620; hg19: chrX-99919476;