chr22-19132265-G-C

Position:

• chr22-19132265-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000252137(ESS2):​c.*1931C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000621 in 1,612,784 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: ESS2 ENST00000252137 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19

Genes affected

TSSK2 (HGNC:11401): (testis specific serine kinase 2) TSSK2 belongs to a family of serine/threonine kinases highly expressed in testis (Hao et al., 2004 [PubMed 15044604]).[supplied by OMIM, Mar 2008]

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007727802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSSK2	NM_053006.5	c.866G>C	p.Gly289Ala	missense_variant	1/1	ENST00000399635.4	NP_443732.3
ESS2	NM_022719.3	c.*1931C>G		3_prime_UTR_variant	10/10	ENST00000252137.11	NP_073210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSSK2	ENST00000399635.4	c.866G>C	p.Gly289Ala	missense_variant	1/1	6	NM_053006.5	ENSP00000382544.2
ESS2	ENST00000252137	c.*1931C>G		3_prime_UTR_variant	10/10	1	NM_022719.3	ENSP00000252137.6

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000519 AC: 129 AN: 248322 Hom.: 1 AF XY: 0.000416 AC XY: 56 AN XY: 134592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.00369

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.000634 AC: 926 AN: 1460528 Hom.: 1 Cov.: 33 AF XY: 0.000613 AC XY: 445 AN XY: 726344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000665

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74456

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000818 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.866G>C (p.G289A) alteration is located in exon 1 (coding exon 1) of the TSSK2 gene. This alteration results from a G to C substitution at nucleotide position 866, causing the glycine (G) at amino acid position 289 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.041
Sift	Benign	0.081	T
Sift4G	Benign	0.34	T
Polyphen		0.0070	B
Vest4		0.21
MVP		0.73
MPC		0.37
ClinPred		0.033	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs141616852; hg19: chr22-19119778;