rs115221221

Positions:

chr2-25742226-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018263.6(ASXL2):c.4111C>A(p.Gln1371Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,613,978 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0038 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 29 hom. )

Consequence

ASXL2
NM_018263.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 9.27

Variant links:

Genes affected

ASXL2 (HGNC:23805): (ASXL transcriptional regulator 2) This gene encodes a member of a family of epigenetic regulators that bind various histone-modifying enzymes and are involved in the assembly of transcription factors at specific genomic loci. Naturally occurring mutations in this gene are associated with cancer in several tissue types (breast, bladder, pancreas, ovary, prostate, and blood). This gene plays an important role in neurodevelopment, cardiac function, adipogenesis, and osteoclastogenesis. [provided by RefSeq, Feb 2017]

ASXL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00520885).

BP6

Variant 2-25742226-G-T is Benign according to our data. Variant chr2-25742226-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 377157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-25742226-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0038 (578/152278) while in subpopulation NFE AF= 0.00356 (242/68030). AF 95% confidence interval is 0.00319. There are 6 homozygotes in gnomad4. There are 365 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 578 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ASXL2	NM_018263.6 linkuse as main transcript	c.4111C>A	p.Gln1371Lys	missense_variant	13/13	ENST00000435504.9	NP_060733.4
ASXL2	NM_001369346.1 linkuse as main transcript	c.3937C>A	p.Gln1313Lys	missense_variant	11/11		NP_001356275.1
ASXL2	NM_001369347.1 linkuse as main transcript	c.3331C>A	p.Gln1111Lys	missense_variant	10/10		NP_001356276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASXL2	ENST00000435504.9 linkuse as main transcript	c.4111C>A	p.Gln1371Lys	missense_variant	13/13	5	NM_018263.6	ENSP00000391447	P4	Q76L83-1
ASXL2	ENST00000336112.9 linkuse as main transcript	c.4108C>A	p.Gln1370Lys	missense_variant	12/12	1		ENSP00000337250	A2
ASXL2	ENST00000404843.5 linkuse as main transcript	c.2560C>A	p.Gln854Lys	missense_variant	10/10	1		ENSP00000383920	A2	Q76L83-2

Frequencies

GnomAD3 genomes

AF:

0.00380

AC:

578

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0274

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00356

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00495

AC:

1235

AN:

249256

Hom.:

AF XY:

0.00482

AC XY:

652

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.000387

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.000696

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.0259

Gnomad NFE exome

AF:

0.00516

Gnomad OTH exome

AF:

0.00529

GnomAD4 exome

AF:

0.00362

AC:

5292

AN:

1461700

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

2583

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00123

Gnomad4 FIN exome

AF:

0.0239

Gnomad4 NFE exome

AF:

0.00329

Gnomad4 OTH exome

AF:

0.00331

GnomAD4 genome

AF:

0.00380

AC:

578

AN:

152278

Hom.:

Cov.:

AF XY:

0.00490

AC XY:

365

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0274

Gnomad4 NFE

AF:

0.00356

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00330

Hom.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000485

AC:

ESP6500EA

AF:

0.00369

AC:

ExAC

AF:

0.00526

AC:

637

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00278

EpiControl

AF:

0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	ASXL2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Shashi-Pena syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;.;.

MutationTaster

Benign

1.0

D;D;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.013

D;D;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.80

P;.;D

Vest4

0.32

MVP

0.15

MPC

0.62

ClinPred

0.042

GERP RS

6.0

Varity_R

0.16

gMVP

0.61

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over