X-100650877-T-C

Variant names:

• chrX-100650877-T-C
• rs73555462
• NM_014467.3:c.163+12T>C

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.163+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,192,175 control chromosomes in the GnomAD database, including 132 homozygotes. There are 1,355 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (79 hom., 635 hem., cov: 22)
  • Exomes 𝑓: 0.0025 (53 hom. 720 hem.)
• Consequence: SRPX2 NM_014467.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.13
• 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: PanelApp Australia, 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=-0.79).
• BP6: Variant X-100650877-T-C is Benign according to our data. Variant chrX-100650877-T-C is described in ClinVar as Benign. ClinVar VariationId is 139327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0719 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.163+12T>C		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.163+12T>C		intron	N/A	ENSP00000362095.3	O60687
	SRPX2	ENST00000638458.1	TSL:5	c.163+12T>C		intron	N/A	ENSP00000492168.1	A0A1W2PR88
	SRPX2	ENST00000640889.1	TSL:5	c.163+12T>C		intron	N/A	ENSP00000492571.1	A0A1W2PRB1

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 2403 AN: 111480 Hom.: 79 Cov.: 22

Gnomad AFR AF: 0.0744

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00846

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000388

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000282

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00624 AC: 1135 AN: 181861 AF XY: 0.00423

Gnomad AFR exome AF: 0.0760

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00378

GnomAD4 exome AF: 0.00254 AC: 2750 AN: 1080637 Hom.: 53 Cov.: 27 AF XY: 0.00208 AC XY: 720 AN XY: 346859

African (AFR) AF: 0.0814 AC: 2121 AN: 26044

American (AMR) AF: 0.00486 AC: 171 AN: 35161

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19279

East Asian (EAS) AF: 0.00 AC: 0 AN: 30133

South Asian (SAS) AF: 0.000448 AC: 24 AN: 53579

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40260

Middle Eastern (MID) AF: 0.00622 AC: 25 AN: 4022

European-Non Finnish (NFE) AF: 0.000204 AC: 169 AN: 826644

Other (OTH) AF: 0.00527 AC: 240 AN: 45515

GnomAD4 genome AF: 0.0216 AC: 2408 AN: 111538 Hom.: 79 Cov.: 22 AF XY: 0.0188 AC XY: 635 AN XY: 33706

African (AFR) AF: 0.0744 AC: 2283 AN: 30681

American (AMR) AF: 0.00845 AC: 89 AN: 10530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3497

South Asian (SAS) AF: 0.000389 AC: 1 AN: 2571

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6072

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.000282 AC: 15 AN: 53118

Other (OTH) AF: 0.0118 AC: 18 AN: 1524

Alfa AF: 0.0116 Hom.: 58

Bravo AF: 0.0256

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Rolandic epilepsy, intellectual disability, and speech dyspraxia, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.6
DANN	Benign	0.60
PhyloP100		2.1
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: rs73555462; hg19: chrX-99905874;