rs115221221

chr2-25742226-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.27

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 578 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASXL2	NM_018263.6	c.4111C>A	p.Gln1371Lys	missense_variant	13/13	ENST00000435504.9
ASXL2	NM_001369346.1	c.3937C>A	p.Gln1313Lys	missense_variant	11/11
ASXL2	NM_001369347.1	c.3331C>A	p.Gln1111Lys	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL2	ENST00000435504.9	c.4111C>A	p.Gln1371Lys	missense_variant	13/13	5	NM_018263.6	P4
ASXL2	ENST00000336112.9	c.4108C>A	p.Gln1370Lys	missense_variant	12/12	1		A2
ASXL2	ENST00000404843.5	c.2560C>A	p.Gln854Lys	missense_variant	10/10	1		A2

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152160 Hom.: 6 Cov.: 32

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.: 11 AF XY: 0.00482 AC XY: 652 AN XY: 135212

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.: 29 Cov.: 32 AF XY: 0.00355 AC XY: 2583 AN XY: 727134

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.: 6 Cov.: 32 AF XY: 0.00490 AC XY: 365 AN XY: 74450

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.: 1

Bravo AF: 0.00182

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000485 AC: 2

ESP6500EA AF: 0.00369 AC: 31

ExAC AF: 0.00526 AC: 637

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ASXL2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -

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	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0052	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.51	T
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	T
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

Other links and lift over

dbSNP: rs115221221; hg19: chr2-25965095; COSMIC: COSV55453434;