X-134793858-C-G

Variant names:

• chrX-134793858-C-G
• rs1447757681
• NM_001387468.1:c.134G>C

Variant summary

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

The NM_001170757.2(PABIR2):​c.-25-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,096,919 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: PABIR2 NM_001170757.2 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• Publications: 0 publications found

Genes affected

PABIR2 (HGNC:30490): (PABIR family member 2) Predicted to enable protein serine/threonine phosphatase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. Predicted to be part of collagen trimer. [provided by Alliance of Genome Resources, Apr 2022]

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_001170757.2. 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
	PABIR2	NM_001387468.1	MANE Select	c.134G>C	p.Arg45Thr	missense	Exon 2 of 10	NP_001374397.1	G1UD79
	PABIR2	NM_001331088.1		c.134G>C	p.Arg45Thr	missense	Exon 2 of 10	NP_001318017.1
	PABIR2	NM_001331089.1		c.134G>C	p.Arg45Thr	missense	Exon 2 of 10	NP_001318018.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PABIR2	ENST00000343004.10	TSL:1 MANE Select	c.134G>C	p.Arg45Thr	missense	Exon 2 of 10	ENSP00000339207.6	G1UD79
	PABIR2	ENST00000370790.5	TSL:1	c.134G>C	p.Arg45Thr	missense	Exon 2 of 9	ENSP00000359826.1	Q7Z309-1
	PABIR2	ENST00000896544.1		c.134G>C	p.Arg45Thr	missense	Exon 2 of 10	ENSP00000566603.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1096919 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362463

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26380

American (AMR) AF: 0.00 AC: 0 AN: 35111

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19362

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39913

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841834

Other (OTH) AF: 0.00 AC: 0 AN: 46069

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.5
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.27
Sift	Benign	0.047	D
Sift4G	Benign	0.085	T
Polyphen		0.73	P
Vest4		0.58
MutPred		0.40		Loss of MoRF binding (P = 0.0148)
MVP		0.58
MPC		1.3
ClinPred		0.30	T
GERP RS		0.73
Varity_R		0.15
gMVP		0.70
Mutation Taster		=86/14	polymorphism

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: rs1447757681; hg19: chrX-133927888;