X-100667342-C-T

Variant names:

• chrX-100667342-C-T
• rs149051060
• NM_014467.3:c.1030C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014467.3(SRPX2):​c.1030C>T​(p.Leu344Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,714 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L344I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SRPX2 NM_014467.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.66
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1030C>T	p.Leu344Phe	missense	Exon 9 of 11	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.1030C>T	p.Leu344Phe	missense	Exon 9 of 11	ENSP00000362095.3	O60687
	SRPX2	ENST00000640282.1	TSL:5	c.76C>T	p.Leu26Phe	missense	Exon 2 of 3	ENSP00000491188.1	A0A1W2PNZ6
	SRPX2	ENST00000638920.1	TSL:5	n.1033C>T		non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097714 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363074

African (AFR) AF: 0.00 AC: 0 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54137

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841645

Other (OTH) AF: 0.00 AC: 0 AN: 46078

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.60		Loss of catalytic residue at L344 (P = 0.0469)
MVP		0.53
MPC		0.70
ClinPred		0.98	D
GERP RS		5.3
PromoterAI		-0.020	Neutral
Varity_R		0.76
gMVP		0.70
Mutation Taster		=33/67	disease causing

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: rs149051060; hg19: chrX-99922339;