dbSNP rs56259360: SRPX2:c.82+243C>T (chrX-100646647-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_014467.3(SRPX2):c.82+243C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 112,017 control chromosomes in the GnomAD database, including 36 homozygotes. There are 614 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.020 ( 36 hom., 614 hem., cov: 23)

Consequence

SRPX2
NM_014467.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.524

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-100646647-C-T is Benign according to our data. Variant chrX-100646647-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 677499.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0202 (2264/112017) while in subpopulation NFE AF = 0.0298 (1587/53187). AF 95% confidence interval is 0.0286. There are 36 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 2264 XLR,XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRPX2	NM_014467.3 link	c.82+243C>T		intron_variant	Intron 2 of 10	ENST00000373004.5	NP_055282.1	O60687

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRPX2	ENST00000373004.5 link	c.82+243C>T		intron_variant	Intron 2 of 10	1	NM_014467.3	ENSP00000362095.3		O60687

Frequencies

GnomAD3 genomes

AF:

0.0202

AC:

2266

AN:

111964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00503

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.0218

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00298

Gnomad FIN

AF:

0.00709

Gnomad MID

AF:

0.0596

Gnomad NFE

AF:

0.0298

Gnomad OTH

AF:

0.0324

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

GnomAD4 genome

AF:

0.0202

AC:

2264

AN:

112017

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

614

AN XY:

34197

show subpopulations

African (AFR)

AF:

0.00501

AC:

155

AN:

30909

American (AMR)

AF:

0.0218

AC:

230

AN:

10555

Ashkenazi Jewish (ASJ)

AF:

0.0378

AC:

100

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3549

South Asian (SAS)

AF:

0.00337

AC:

AN:

2673

European-Finnish (FIN)

AF:

0.00709

AC:

AN:

6066

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.0298

AC:

1587

AN:

53187

Other (OTH)

AF:

0.0320

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0241

Hom.:

144

Bravo

AF:

0.0211

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 14, 2018

GeneDx

Significance:Likely 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

-0.83

CADD

Benign

1.1

(source)

DANN

Benign

0.61

PhyloP100

-0.52

PromoterAI

-0.020

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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rs56259360

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over