rs2233697

Variant names:

• chrX-103785745-A-G
• rs2233697
• NM_000533.5:c.168A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BS1 BS2

The NM_001305004.1(PLP1):​c.5-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,207,098 control chromosomes in the GnomAD database, including 10 homozygotes. There are 551 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., 59 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (8 hom. 492 hem.)
• Consequence: PLP1 NM_001305004.1 splice_acceptor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.15
• Publications: 5 publications found

Genes affected

PLP1 (HGNC:9086): (proteolipid protein 1) This gene encodes a transmembrane proteolipid protein that is the predominant component of myelin. The encoded protein may play a role in the compaction, stabilization, and maintenance of myelin sheaths, as well as in oligodendrocyte development and axonal survival. Mutations in this gene cause Pelizaeus-Merzbacher disease and spastic paraplegia type 2. Alternatively splicing results in multiple transcript variants, including the DM20 splice variant. [provided by RefSeq, Feb 2015]

ENSG00000288597 (HGNC:):

RAB9B (HGNC:14090): (RAB9B, member RAS oncogene family) This gene encodes a member of a subfamily of RAS small guanosine triphosphate (GTP)-binding proteins that regulate membrane trafficking. The encoded protein may be involved in endosome-to-Golgi transport. [provided by RefSeq, Jan 2010]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.1, offset of -1, new splice context is: atttctccaaaaactaccAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant X-103785745-A-G is Benign according to our data. Variant chrX-103785745-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00184 (206/111795) while in subpopulation EAS AF = 0.0207 (73/3520). AF 95% confidence interval is 0.0169. There are 2 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001305004.1. 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
	PLP1	NM_000533.5	MANE Select	c.168A>G	p.Gln56Gln	synonymous	Exon 2 of 7	NP_000524.3
	PLP1	NM_001128834.3		c.168A>G	p.Gln56Gln	synonymous	Exon 3 of 8	NP_001122306.1
	PLP1	NM_199478.3		c.168A>G	p.Gln56Gln	synonymous	Exon 2 of 7	NP_955772.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLP1	ENST00000621218.5	TSL:1 MANE Select	c.168A>G	p.Gln56Gln	synonymous	Exon 2 of 7	ENSP00000484450.1
	PLP1	ENST00000619236.1	TSL:1	c.168A>G	p.Gln56Gln	synonymous	Exon 2 of 7	ENSP00000477619.1
	PLP1	ENST00000867712.1		c.168A>G	p.Gln56Gln	synonymous	Exon 2 of 8	ENSP00000537771.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 197 AN: 111741 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00755

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0207

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.000815

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000414

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00347 AC: 636 AN: 183425 AF XY: 0.00261

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0184

Gnomad FIN exome AF: 0.000812

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00143 AC: 1569 AN: 1095303 Hom.: 8 Cov.: 29 AF XY: 0.00136 AC XY: 492 AN XY: 360697

African (AFR) AF: 0.000152 AC: 4 AN: 26344

American (AMR) AF: 0.0123 AC: 432 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.0226 AC: 681 AN: 30197

South Asian (SAS) AF: 0.00115 AC: 62 AN: 54087

European-Finnish (FIN) AF: 0.00168 AC: 68 AN: 40530

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4133

European-Non Finnish (NFE) AF: 0.000275 AC: 231 AN: 839444

Other (OTH) AF: 0.00196 AC: 90 AN: 45997

GnomAD4 genome AF: 0.00184 AC: 206 AN: 111795 Hom.: 2 Cov.: 23 AF XY: 0.00173 AC XY: 59 AN XY: 34007

African (AFR) AF: 0.000228 AC: 7 AN: 30741

American (AMR) AF: 0.00745 AC: 79 AN: 10611

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.0207 AC: 73 AN: 3520

South Asian (SAS) AF: 0.00189 AC: 5 AN: 2644

European-Finnish (FIN) AF: 0.000815 AC: 5 AN: 6132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000414 AC: 22 AN: 53080

Other (OTH) AF: 0.00988 AC: 15 AN: 1518

Alfa AF: 0.00170 Hom.: 16

Bravo AF: 0.00235

EpiCase AF: 0.000491

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia 2 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Pelizaeus-Merzbacher disease;C1839264:Hereditary spastic paraplegia 2 (1)
-	-	1	PLP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.7
DANN	Benign	0.61
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2233697; hg19: chrX-103040674; COSMIC: COSV58275905; COSMIC: COSV58275905;