Genetic Variant GSX2:p.His136His (chr4-54100752-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_133267.3(GSX2):c.408T>C(p.His136His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 1,542,290 control chromosomes in the GnomAD database, including 297,211 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 24960 hom., cov: 33)

Exomes 𝑓: 0.62 ( 272251 hom. )

Consequence

GSX2
NM_133267.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.808

Variant links:

Genes affected

GSX2 (HGNC:24959): (GS homeobox 2) Enables DNA-binding transcription factor activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including nervous system development; positive regulation of Notch signaling pathway; and regulation of respiratory gaseous exchange by nervous system process. Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

GSX2 links:

ENSG00000282278 (HGNC:):

ENSG00000282278 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 4-54100752-T-C is Benign according to our data. Variant chr4-54100752-T-C is described in ClinVar as [Benign]. Clinvar id is 1223318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.808 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GSX2	NM_133267.3 link	c.408T>C	p.His136His	synonymous_variant	Exon 1 of 2	ENST00000326902.7	NP_573574.2	Q9BZM3B2LYG3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GSX2	ENST00000326902.7 link	c.408T>C	p.His136His	synonymous_variant	Exon 1 of 2	1	NM_133267.3	ENSP00000319118.2	Q9BZM3
ENSG00000282278	ENST00000507166.5 link	c.1018-174173T>C		intron_variant	Intron 12 of 23	2		ENSP00000423325.1	A0A0B4J203
GSX2	ENST00000503800.1 link	c.363+45T>C		intron_variant	Intron 1 of 1	5		ENSP00000422213.1	D6R903
GSX2	ENST00000507839.1 link	n.115-830T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.555

AC:

84187

AN:

151704

Hom.:

24948

Cov.:

show subpopulations

Gnomad AFR

AF:

0.341

Gnomad AMI

AF:

0.736

Gnomad AMR

AF:

0.667

Gnomad ASJ

AF:

0.553

Gnomad EAS

AF:

0.832

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.646

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.616

Gnomad OTH

AF:

0.566

GnomAD3 exomes

AF:

0.652

AC:

90603

AN:

138900

Hom.:

30323

AF XY:

0.649

AC XY:

48638

AN XY:

74998

show subpopulations

Gnomad AFR exome

AF:

0.347

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.557

Gnomad EAS exome

AF:

0.840

Gnomad SAS exome

AF:

0.634

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.624

Gnomad OTH exome

AF:

0.635

GnomAD4 exome

AF:

0.622

AC:

865244

AN:

1390480

Hom.:

272251

Cov.:

AF XY:

0.623

AC XY:

427368

AN XY:

686024

show subpopulations

Gnomad4 AFR exome

AF:

0.328

Gnomad4 AMR exome

AF:

0.753

Gnomad4 ASJ exome

AF:

0.554

Gnomad4 EAS exome

AF:

0.825

Gnomad4 SAS exome

AF:

0.635

Gnomad4 FIN exome

AF:

0.646

Gnomad4 NFE exome

AF:

0.620

Gnomad4 OTH exome

AF:

0.618

GnomAD4 genome

AF:

0.555

AC:

84211

AN:

151810

Hom.:

24960

Cov.:

AF XY:

0.561

AC XY:

41607

AN XY:

74194

show subpopulations

Gnomad4 AFR

AF:

0.340

Gnomad4 AMR

AF:

0.668

Gnomad4 ASJ

AF:

0.553

Gnomad4 EAS

AF:

0.831

Gnomad4 SAS

AF:

0.650

Gnomad4 FIN

AF:

0.646

Gnomad4 NFE

AF:

0.616

Gnomad4 OTH

AF:

0.569

Alfa

AF:

0.598

Hom.:

8941

Bravo

AF:

0.549

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diencephalic-mesencephalic junction dysplasia syndrome 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.1

DANN

Benign

0.62

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