chr19-7619641-C-T

Variant names:

• chr19-7619641-C-T
• rs144798612
• NM_020196.3:c.2513G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_020196.3(XAB2):​c.2513G>A​(p.Arg838Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,603,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R838W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: XAB2 NM_020196.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18
• Publications: 1 publications found

Genes affected

XAB2 (HGNC:14089): (XPA binding protein 2) Involved in mRNA splicing, via spliceosome; transcription, DNA-templated; and transcription-coupled nucleotide-excision repair. Located in nucleoplasm. Part of U2-type catalytic step 2 spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.027380496).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020196.3. 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
	XAB2	NM_020196.3	MANE Select	c.2513G>A	p.Arg838Gln	missense	Exon 19 of 19	NP_064581.2	Q9HCS7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XAB2	ENST00000358368.5	TSL:1 MANE Select	c.2513G>A	p.Arg838Gln	missense	Exon 19 of 19	ENSP00000351137.3	Q9HCS7
	XAB2	ENST00000925818.1		c.2543G>A	p.Arg848Gln	missense	Exon 19 of 19	ENSP00000595877.1
	XAB2	ENST00000925815.1		c.2510G>A	p.Arg837Gln	missense	Exon 19 of 19	ENSP00000595874.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000167 AC: 4 AN: 240012 AF XY: 0.0000154

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: 0.0000280

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1451584 Hom.: 0 Cov.: 36 AF XY: 0.0000139 AC XY: 10 AN XY: 720982

African (AFR) AF: 0.0000300 AC: 1 AN: 33362

American (AMR) AF: 0.0000226 AC: 1 AN: 44170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39606

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84808

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1106514

Other (OTH) AF: 0.00 AC: 0 AN: 59904

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000347 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

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	0.065
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	N
PhyloP100		2.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.68	N
REVEL	Benign	0.10
Sift	Benign	0.72	T
Sift4G	Benign	0.79	T
Polyphen		0.013	B
Vest4		0.16
MutPred		0.20		Loss of sheet (P = 0.1158)
MVP		0.068
MPC		0.59
ClinPred		0.092	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.026
gMVP		0.17
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs144798612; hg19: chr19-7684527;