chrX-100664736-G-A

Variant names:

• chrX-100664736-G-A
• rs2022475
• NM_014467.3:c.356-38G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_014467.3(SRPX2):​c.356-38G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (28043 hom., 27378 hem., cov: 23)
  • Exomes 𝑓: 0.95 (330570 hom. 327549 hem.)
  • Failed GnomAD Quality Control
• Consequence: SRPX2 NM_014467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.07
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-100664736-G-A is Benign according to our data. Variant chrX-100664736-G-A is described in ClinVar as Benign. ClinVar VariationId is 670790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3	c.356-38G>A		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.356-38G>A		intron_variant	Intron 4 of 10	1	NM_014467.3	ENSP00000362095.3

Frequencies

GnomAD3 genomes AF: 0.820 AC: 90935 AN: 110961 Hom.: 28058 Cov.: 23

Gnomad AFR AF: 0.455

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.913

Gnomad ASJ AF: 0.975

Gnomad EAS AF: 0.845

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.990

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.977

Gnomad OTH AF: 0.864

GnomAD2 exomes AF: 0.907 AC: 124705 AN: 137432 AF XY: 0.913

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.933

Gnomad ASJ exome AF: 0.972

Gnomad EAS exome AF: 0.838

Gnomad FIN exome AF: 0.988

Gnomad NFE exome AF: 0.978

Gnomad OTH exome AF: 0.944

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.952 AC: 1015110 AN: 1066367 Hom.: 330570 Cov.: 29 AF XY: 0.951 AC XY: 327549 AN XY: 344355

African (AFR) AF: 0.441 AC: 11268 AN: 25535

American (AMR) AF: 0.929 AC: 28758 AN: 30957

Ashkenazi Jewish (ASJ) AF: 0.971 AC: 18391 AN: 18938

East Asian (EAS) AF: 0.848 AC: 24412 AN: 28800

South Asian (SAS) AF: 0.849 AC: 43180 AN: 50858

European-Finnish (FIN) AF: 0.988 AC: 38009 AN: 38486

Middle Eastern (MID) AF: 0.914 AC: 3472 AN: 3799

European-Non Finnish (NFE) AF: 0.978 AC: 806172 AN: 824031

Other (OTH) AF: 0.922 AC: 41448 AN: 44963

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.819 AC: 90935 AN: 111013 Hom.: 28043 Cov.: 23 AF XY: 0.824 AC XY: 27378 AN XY: 33235

African (AFR) AF: 0.455 AC: 13853 AN: 30459

American (AMR) AF: 0.913 AC: 9552 AN: 10464

Ashkenazi Jewish (ASJ) AF: 0.975 AC: 2578 AN: 2644

East Asian (EAS) AF: 0.845 AC: 2942 AN: 3482

South Asian (SAS) AF: 0.833 AC: 2155 AN: 2587

European-Finnish (FIN) AF: 0.990 AC: 5831 AN: 5892

Middle Eastern (MID) AF: 0.930 AC: 198 AN: 213

European-Non Finnish (NFE) AF: 0.977 AC: 51839 AN: 53076

Other (OTH) AF: 0.862 AC: 1302 AN: 1511

Alfa AF: 0.878 Hom.: 85487

Bravo AF: 0.801

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 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. -

Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.49
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2022475; hg19: chrX-99919733; COSMIC: COSV65933652; COSMIC: COSV65933652;