2-25767771-T-C

Variant names:

• chr2-25767771-T-C
• rs17680828
• NM_018263.6:c.632-45A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018263.6(ASXL2):​c.632-45A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,598,202 control chromosomes in the GnomAD database, including 33,819 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2174 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31645 hom.)
• Consequence: ASXL2 NM_018263.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.337
• Publications: 8 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: Labcorp Genetics (formerly Invitae), G2P, Illumina

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASXL2	NM_018263.6	c.632-45A>G		intron_variant	Intron 7 of 12	ENST00000435504.9	NP_060733.4
ASXL2	NM_001369346.1	c.458-45A>G		intron_variant	Intron 5 of 10		NP_001356275.1
ASXL2	NM_001369347.1	c.-149-45A>G		intron_variant	Intron 4 of 9		NP_001356276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASXL2	ENST00000435504.9	c.632-45A>G		intron_variant	Intron 7 of 12	5	NM_018263.6	ENSP00000391447.3
ASXL2	ENST00000336112.9	c.629-45A>G		intron_variant	Intron 6 of 11	1		ENSP00000337250.5
ASXL2	ENST00000404843.5	c.-149-45A>G		intron_variant	Intron 3 of 9	1		ENSP00000383920.1
ASXL2	ENST00000673455.1	c.-149-45A>G		intron_variant	Intron 4 of 9			ENSP00000500467.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22989 AN: 152166 Hom.: 2166 Cov.: 33

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0861

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.166 AC: 40550 AN: 244364 AF XY: 0.168

Gnomad AFR exome AF: 0.0434

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0899

Gnomad FIN exome AF: 0.169

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.203 AC: 293550 AN: 1445916 Hom.: 31645 Cov.: 27 AF XY: 0.201 AC XY: 144936 AN XY: 719358

African (AFR) AF: 0.0393 AC: 1297 AN: 32966

American (AMR) AF: 0.115 AC: 5012 AN: 43682

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 3982 AN: 25688

East Asian (EAS) AF: 0.0664 AC: 2625 AN: 39536

South Asian (SAS) AF: 0.157 AC: 13373 AN: 85156

European-Finnish (FIN) AF: 0.171 AC: 9041 AN: 52802

Middle Eastern (MID) AF: 0.126 AC: 720 AN: 5694

European-Non Finnish (NFE) AF: 0.224 AC: 246412 AN: 1100640

Other (OTH) AF: 0.186 AC: 11088 AN: 59752

GnomAD4 genome AF: 0.151 AC: 23021 AN: 152286 Hom.: 2174 Cov.: 33 AF XY: 0.148 AC XY: 11039 AN XY: 74476

African (AFR) AF: 0.0478 AC: 1986 AN: 41566

American (AMR) AF: 0.146 AC: 2236 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3470

East Asian (EAS) AF: 0.0861 AC: 447 AN: 5192

South Asian (SAS) AF: 0.165 AC: 797 AN: 4832

European-Finnish (FIN) AF: 0.162 AC: 1716 AN: 10608

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14782 AN: 68004

Other (OTH) AF: 0.157 AC: 332 AN: 2116

Alfa AF: 0.179 Hom.: 1013

Bravo AF: 0.145

Asia WGS AF: 0.173 AC: 603 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.4
DANN	Benign	0.80
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

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: rs17680828; hg19: chr2-25990640; COSMIC: COSV55458403; COSMIC: COSV55458403;