X-14690691-GTCTCTC-GTCTCTCTCTC

Variant names:

• chrX-14690691-G-GTCTC
• rs752610633
• NM_002063.4:c.931-6_931-3dupTCTC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS2

The NM_002063.4(GLRA2):​c.931-6_931-3dupTCTC variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000396 in 924,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (0 hom. 69 hem.)
• Consequence: GLRA2 NM_002063.4 splice_acceptor, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.590
• Publications: 0 publications found

Genes affected

GLRA2 (HGNC:4327): (glycine receptor alpha 2) The glycine receptor consists of two subunits, alpha and beta, and acts as a pentamer. The protein encoded by this gene is an alpha subunit and can bind strychnine. Several transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

FANCB Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• VACTERL association, X-linked, with or without hydrocephalus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• VACTERL with hydrocephalus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11037528 fraction of the gene. Cryptic splice site detected, with MaxEntScore 14, offset of 0 (no position change), new splice context is: tctctctctctctctctcAGgtc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant X-14690691-G-GTCTC is Benign according to our data. Variant chrX-14690691-G-GTCTC is described in ClinVar as Likely_benign. ClinVar VariationId is 3054739.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 9 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002063.4. 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
	GLRA2	NM_002063.4	MANE Select	c.931-6_931-3dupTCTC		splice_acceptor intron	N/A	NP_002054.1	P23416-1
	GLRA2	NM_001118885.2		c.931-6_931-3dupTCTC		splice_acceptor intron	N/A	NP_001112357.1	P23416-1
	GLRA2	NM_001118886.2		c.931-6_931-3dupTCTC		splice_acceptor intron	N/A	NP_001112358.1	P23416-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLRA2	ENST00000218075.9	TSL:1 MANE Select	c.931-6_931-3dupTCTC		splice_acceptor intron	N/A	ENSP00000218075.4	P23416-1
	GLRA2	ENST00000355020.9	TSL:1	c.931-6_931-3dupTCTC		splice_acceptor intron	N/A	ENSP00000347123.4	P23416-2
	FANCB	ENST00000696351.1		n.*927_*930dupGAGA		non_coding_transcript_exon	Exon 15 of 15	ENSP00000512572.1	A0A8Q3SJA8

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 38 AN: 109130 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000671

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000668

Gnomad OTH AF: 0.000691

GnomAD2 exomes AF: 0.000314 AC: 39 AN: 124260 AF XY: 0.000257

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000640

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000402 AC: 328 AN: 815601 Hom.: 0 Cov.: 15 AF XY: 0.000290 AC XY: 69 AN XY: 237923

African (AFR) AF: 0.00 AC: 0 AN: 20512

American (AMR) AF: 0.0000652 AC: 2 AN: 30669

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15569

East Asian (EAS) AF: 0.00 AC: 0 AN: 25853

South Asian (SAS) AF: 0.00 AC: 0 AN: 43335

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3198

European-Non Finnish (NFE) AF: 0.000505 AC: 306 AN: 605738

Other (OTH) AF: 0.000568 AC: 20 AN: 35208

GnomAD4 genome AF: 0.000348 AC: 38 AN: 109173 Hom.: 0 Cov.: 23 AF XY: 0.000282 AC XY: 9 AN XY: 31911

African (AFR) AF: 0.0000669 AC: 2 AN: 29874

American (AMR) AF: 0.00 AC: 0 AN: 10222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2599

East Asian (EAS) AF: 0.00 AC: 0 AN: 3500

South Asian (SAS) AF: 0.00 AC: 0 AN: 2550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.000668 AC: 35 AN: 52411

Other (OTH) AF: 0.000682 AC: 1 AN: 1467

Alfa AF: 0.0000870 Hom.: 0

Bravo AF: 0.000264

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	GLRA2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs752610633; hg19: chrX-14708813;