rs2182721

Variant names:

• chrX-68047997-T-C
• rs2182721
• NM_002547.3:c.*8+419A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002547.3(OPHN1):​c.*8+419A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 110,891 control chromosomes in the GnomAD database, including 2,967 homozygotes. There are 6,466 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.21 (2967 hom., 6466 hem., cov: 22)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470
• Publications: 1 publications found

Genes affected

OPHN1 (HGNC:8148): (oligophrenin 1) This gene encodes a Rho-GTPase-activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Mutations in this gene are responsible for OPHN1-related X-linked cognitive disability with cerebellar hypoplasia and distinctive facial dysmorhphism. [provided by RefSeq, Jul 2008]

OPHN1 Gene-Disease associations (from GenCC):

• X-linked intellectual disability-cerebellar hypoplasia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3	c.*8+419A>G		intron_variant	Intron 24 of 24	ENST00000355520.6	NP_002538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6	c.*8+419A>G		intron_variant	Intron 24 of 24	1	NM_002547.3	ENSP00000347710.5

Frequencies

GnomAD3 genomes AF: 0.207 AC: 22984 AN: 110834 Hom.: 2957 Cov.: 22

Gnomad AFR AF: 0.467

Gnomad AMI AF: 0.0234

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0805

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.208 AC: 23039 AN: 110891 Hom.: 2967 Cov.: 22 AF XY: 0.195 AC XY: 6466 AN XY: 33139

African (AFR) AF: 0.468 AC: 14141 AN: 30235

American (AMR) AF: 0.211 AC: 2200 AN: 10442

Ashkenazi Jewish (ASJ) AF: 0.0761 AC: 201 AN: 2640

East Asian (EAS) AF: 0.286 AC: 988 AN: 3459

South Asian (SAS) AF: 0.241 AC: 623 AN: 2584

European-Finnish (FIN) AF: 0.0387 AC: 235 AN: 6072

Middle Eastern (MID) AF: 0.134 AC: 29 AN: 217

European-Non Finnish (NFE) AF: 0.0805 AC: 4272 AN: 53053

Other (OTH) AF: 0.222 AC: 334 AN: 1505

Alfa AF: 0.222 Hom.: 5591

Bravo AF: 0.239

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.58
PhyloP100		0.047
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: rs2182721; hg19: chrX-67267839;