Variant 2-25742167-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_018263.6(ASXL2):c.4170G>C(p.Glu1390Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ASXL2
NM_018263.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.163

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039406806).

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ASXL2	NM_018263.6 linkuse as main transcript	c.4170G>C	p.Glu1390Asp	missense_variant	13/13	ENST00000435504.9
ASXL2	NM_001369346.1 linkuse as main transcript	c.3996G>C	p.Glu1332Asp	missense_variant	11/11
ASXL2	NM_001369347.1 linkuse as main transcript	c.3390G>C	p.Glu1130Asp	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASXL2	ENST00000435504.9 linkuse as main transcript	c.4170G>C	p.Glu1390Asp	missense_variant	13/13	5	NM_018263.6	P4	Q76L83-1
ASXL2	ENST00000336112.9 linkuse as main transcript	c.4167G>C	p.Glu1389Asp	missense_variant	12/12	1		A2
ASXL2	ENST00000404843.5 linkuse as main transcript	c.2619G>C	p.Glu873Asp	missense_variant	10/10	1		A2	Q76L83-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 03, 2024

Variant summary: ASXL2 c.4170G>C (p.Glu1390Asp) results in a conservative amino acid change located in the Protein ASX-like, PHD domain (IPR026905) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4170G>C in individuals affected with Shashi-Pena Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.8

DANN

Benign

0.29

DEOGEN2

Benign

0.047

T;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.039

T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

0.0

N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.32

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.41

T;T;T

Sift4G

Benign

0.58

T;T;T

Polyphen

0.0030

B;.;P

Vest4

0.041

MutPred

0.16

Loss of glycosylation at S1392 (P = 0.1201);.;.;

MVP

0.21

MPC

0.16

ClinPred

0.062

GERP RS

-0.72

Varity_R

0.078

gMVP

0.20

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