chrX-100664569-C-A

Variant names:

• chrX-100664569-C-A
• rs36224186
• NM_014467.3:c.356-205C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014467.3(SRPX2):​c.356-205C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0888 in 111,259 control chromosomes in the GnomAD database, including 899 homozygotes. There are 2,801 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.089 (899 hom., 2801 hem., cov: 23)
• Consequence: SRPX2 NM_014467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05
• 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)
• epilepsy

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-100664569-C-A is Benign according to our data. Variant chrX-100664569-C-A is described in ClinVar as Benign. ClinVar VariationId is 1229905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRPX2	NM_014467.3	MANE Select	c.356-205C>A		intron	N/A	NP_055282.1	O60687

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRPX2	ENST00000373004.5	TSL:1 MANE Select	c.356-205C>A		intron	N/A	ENSP00000362095.3	O60687
	SRPX2	ENST00000638458.1	TSL:5	c.380-205C>A		intron	N/A	ENSP00000492168.1	A0A1W2PR88
	SRPX2	ENST00000640889.1	TSL:5	c.356-205C>A		intron	N/A	ENSP00000492571.1	A0A1W2PRB1

Frequencies

GnomAD3 genomes AF: 0.0886 AC: 9851 AN: 111209 Hom.: 895 Cov.: 23

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.000673

Gnomad MID AF: 0.0504

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.0673

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

GnomAD4 genome AF: 0.0888 AC: 9882 AN: 111259 Hom.: 899 Cov.: 23 AF XY: 0.0836 AC XY: 2801 AN XY: 33495

African (AFR) AF: 0.266 AC: 8087 AN: 30454

American (AMR) AF: 0.0486 AC: 510 AN: 10491

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 58 AN: 2644

East Asian (EAS) AF: 0.143 AC: 506 AN: 3531

South Asian (SAS) AF: 0.128 AC: 334 AN: 2619

European-Finnish (FIN) AF: 0.000673 AC: 4 AN: 5943

Middle Eastern (MID) AF: 0.0419 AC: 9 AN: 215

European-Non Finnish (NFE) AF: 0.00504 AC: 268 AN: 53159

Other (OTH) AF: 0.0698 AC: 106 AN: 1519

Alfa AF: 0.0639 Hom.: 253

Bravo AF: 0.101

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.14
DANN	Benign	0.49
PhyloP100		-2.0
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: rs36224186; hg19: chrX-99919566;