Genetic Variant ESS2:c.-172T>C (chr22-19144812-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_022719.3(ESS2):c.-172T>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.38 in 1,073,982 control chromosomes in the GnomAD database, including 81,214 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 0.41 ( 13432 hom., cov: 32)

Exomes 𝑓: 0.37 ( 67782 hom. )

Consequence

ESS2
NM_022719.3 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.54

Publications

14 publications found

Variant links:

Genes affected

ESS2 (HGNC:16817): (ess-2 splicing factor homolog) This gene is located within the minimal DGS critical region (MDGCR) thought to contain the gene(s) responsible for a group of developmental disorders. These disorders include DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and some familial or sporadic conotruncal cardiac defects which have been associated with microdeletion of 22q11.2. The encoded protein may be a component of C complex spliceosomes, and the orthologous protein in the mouse localizes to the nucleus. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

ESS2 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESS2	NM_022719.3 link	c.-172T>C		upstream_gene_variant		ENST00000252137.11	NP_073210.1	Q96DF8

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
ESS2	ENST00000252137.11 link	c.-172T>C	upstream_gene_variant	1	NM_022719.3	ENSP00000252137.6	Q96DF8
ESS2	ENST00000434568.5 link	n.-172T>C	upstream_gene_variant	5		ENSP00000388524.1	F8WEF8
ESS2	ENST00000469466.1 link	n.-153T>C	upstream_gene_variant	3
ESS2	ENST00000472073.1 link	n.-179T>C	upstream_gene_variant	5

Frequencies

GnomAD3 genomes

AF:

0.413

AC:

62734

AN:

151970

Hom.:

13390

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.416

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.690

Gnomad SAS

AF:

0.491

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.363

Gnomad OTH

AF:

0.404

GnomAD4 exome

AF:

0.375

AC:

345385

AN:

921894

Hom.:

67782

AF XY:

0.377

AC XY:

170305

AN XY:

451982

show subpopulations

African (AFR)

AF:

0.464

AC:

8697

AN:

18724

American (AMR)

AF:

0.393

AC:

4616

AN:

11734

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

5653

AN:

14930

East Asian (EAS)

AF:

0.736

AC:

19462

AN:

26442

South Asian (SAS)

AF:

0.459

AC:

19368

AN:

42188

European-Finnish (FIN)

AF:

0.390

AC:

10796

AN:

27698

Middle Eastern (MID)

AF:

0.379

AC:

1053

AN:

2778

European-Non Finnish (NFE)

AF:

0.353

AC:

260297

AN:

737838

Other (OTH)

AF:

0.390

AC:

15443

AN:

39562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

10272

20544

30816

41088

51360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8452

16904

25356

33808

42260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.413

AC:

62838

AN:

152088

Hom.:

13432

Cov.:

AF XY:

0.419

AC XY:

31123

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.461

AC:

19139

AN:

41494

American (AMR)

AF:

0.417

AC:

6366

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1321

AN:

3472

East Asian (EAS)

AF:

0.690

AC:

3558

AN:

5156

South Asian (SAS)

AF:

0.491

AC:

2370

AN:

4826

European-Finnish (FIN)

AF:

0.404

AC:

4268

AN:

10566

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.363

AC:

24647

AN:

67978

Other (OTH)

AF:

0.411

AC:

865

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1827

3654

5481

7308

9135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

600

1200

1800

2400

3000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.381

Hom.:

30701

Bravo

AF:

0.412

Asia WGS

AF:

0.596

AC:

2071

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.56

(source)

DANN

Benign

0.75

PhyloP100

-1.5

PromoterAI

-0.081

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over