rs115221221

Variant names:

• chr2-25742226-G-T
• rs115221221
• NM_018263.6:c.4111C>A

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 9.27
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Shashi-Pena syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 377157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 578 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018263.6. 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
	ASXL2	NM_018263.6	MANE Select	c.4111C>A	p.Gln1371Lys	missense	Exon 13 of 13	NP_060733.4
	ASXL2	NM_001369346.1		c.3937C>A	p.Gln1313Lys	missense	Exon 11 of 11	NP_001356275.1
	ASXL2	NM_001369347.1		c.3331C>A	p.Gln1111Lys	missense	Exon 10 of 10	NP_001356276.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASXL2	ENST00000435504.9	TSL:5 MANE Select	c.4111C>A	p.Gln1371Lys	missense	Exon 13 of 13	ENSP00000391447.3	Q76L83-1
	ASXL2	ENST00000336112.9	TSL:1	c.4108C>A	p.Gln1370Lys	missense	Exon 12 of 12	ENSP00000337250.5	E7EWD6
	ASXL2	ENST00000404843.5	TSL:1	c.2560C>A	p.Gln854Lys	missense	Exon 10 of 10	ENSP00000383920.1	Q76L83-2

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

GnomAD2 exomes AF: 0.00495 AC: 1235 AN: 249256 AF XY: 0.00482

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 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

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00123 AC: 106 AN: 86254

European-Finnish (FIN) AF: 0.0239 AC: 1278 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00329 AC: 3659 AN: 1111864

Other (OTH) AF: 0.00331 AC: 200 AN: 60374

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152278 Hom.: 6 Cov.: 32 AF XY: 0.00490 AC XY: 365 AN XY: 74450

African (AFR) AF: 0.000505 AC: 21 AN: 41562

American (AMR) AF: 0.000720 AC: 11 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0274 AC: 291 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00335 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Shashi-Pena syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Benign	1.0	T
Polyphen		0.80	P
Vest4		0.32
MVP		0.15
MPC		0.62
ClinPred		0.042	T
GERP RS		6.0
Varity_R		0.16
gMVP		0.61
Mutation Taster		=98/2	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: rs115221221; hg19: chr2-25965095; COSMIC: COSV55453434;