3-122338016-T-G

Variant names:

• chr3-122338016-T-G
• rs9842752
• NM_005213.4:c.168+368T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005213.4(CSTA):​c.168+368T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSTA NM_005213.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.13
• Publications: 4 publications found

Genes affected

CSTA (HGNC:2481): (cystatin A) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer. [provided by RefSeq, Jul 2008]

CSTA Gene-Disease associations (from GenCC):

• peeling skin syndrome 4

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• acral peeling skin syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• exfoliative ichthyosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTA	NM_005213.4	c.168+368T>G		intron_variant	Intron 2 of 2	ENST00000264474.4	NP_005204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTA	ENST00000264474.4	c.168+368T>G		intron_variant	Intron 2 of 2	1	NM_005213.4	ENSP00000264474.3
CSTA	ENST00000479204.1	c.*344T>G		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000418891.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 44850 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 23700

African (AFR) AF: 0.00 AC: 0 AN: 996

American (AMR) AF: 0.00 AC: 0 AN: 2292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1260

East Asian (EAS) AF: 0.00 AC: 0 AN: 1830

South Asian (SAS) AF: 0.00 AC: 0 AN: 6510

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 170

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 27096

Other (OTH) AF: 0.00 AC: 0 AN: 2560

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.50
PhyloP100		-3.1

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

Other links and lift over

dbSNP: rs9842752; hg19: chr3-122056863;