22-26594843-A-G

Variant names:

• chr22-26594843-A-G
• rs5752351
• ENST00000403880.5:c.-331+1784T>C

Variant summary

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

The ENST00000403880.5(TPST2):​c.-331+1784T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 152,184 control chromosomes in the GnomAD database, including 3,318 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 0.20 (3318 hom., cov: 32)
• Consequence: TPST2 ENST00000403880.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 6 publications found

Genes affected

TPST2 (HGNC:12021): (tyrosylprotein sulfotransferase 2) The protein encoded by this gene catalyzes the O-sulfation of tyrosine residues within acidic regions of proteins. The encoded protein is a type II integral membrane protein found in the Golgi body. Alternative splicing produces multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2018]

ENSG00000286326 (HGNC:):

CRYBA4 (HGNC:2396): (crystallin beta A4) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta acidic group member, is part of a gene cluster with beta-B1, beta-B2, and beta-B3. [provided by RefSeq, Jul 2008]

CRYBA4 Gene-Disease associations (from GenCC):

• cataract 23

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBA4	XM_006724140.4	c.-328-2151A>G		intron_variant	Intron 1 of 7		XP_006724203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPST2	ENST00000403880.5	c.-331+1784T>C		intron_variant	Intron 1 of 7	5		ENSP00000385192.1
ENSG00000286326	ENST00000840229.1	n.145-2151A>G		intron_variant	Intron 1 of 2
ENSG00000286326	ENST00000840230.1	n.145-2151A>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30627 AN: 152066 Hom.: 3318 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.196

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.201 AC: 30649 AN: 152184 Hom.: 3318 Cov.: 32 AF XY: 0.205 AC XY: 15255 AN XY: 74392

African (AFR) AF: 0.222 AC: 9206 AN: 41514

American (AMR) AF: 0.209 AC: 3197 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.236 AC: 821 AN: 3472

East Asian (EAS) AF: 0.402 AC: 2079 AN: 5170

South Asian (SAS) AF: 0.311 AC: 1501 AN: 4820

European-Finnish (FIN) AF: 0.203 AC: 2154 AN: 10598

Middle Eastern (MID) AF: 0.175 AC: 51 AN: 292

European-Non Finnish (NFE) AF: 0.162 AC: 11044 AN: 68000

Other (OTH) AF: 0.198 AC: 419 AN: 2116

Alfa AF: 0.177 Hom.: 9852

Bravo AF: 0.199

Asia WGS AF: 0.331 AC: 1148 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.99
DANN	Benign	0.45
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs5752351; hg19: chr22-26990807;