Genetic Variant NM_005213.4:c.64A>G (chr3-122325356-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005213.4(CSTA):c.64A>G(p.Lys22Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CSTA
NM_005213.4 missense, splice_region

Scores

Splicing: ADA: 0.0002997

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.38

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=0.062099367).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTA	NM_005213.4 link	c.64A>G	p.Lys22Glu	missense_variant, splice_region_variant	Exon 1 of 3	ENST00000264474.4	NP_005204.1	P01040

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTA	ENST00000264474.4 link	c.64A>G	p.Lys22Glu	missense_variant, splice_region_variant	Exon 1 of 3	1	NM_005213.4	ENSP00000264474.3		P01040
CSTA	ENST00000479204.1 link	c.64A>G	p.Lys22Glu	missense_variant, splice_region_variant	Exon 1 of 2	2		ENSP00000418891.1		C9J0E4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.69

DANN

Benign

0.80

DEOGEN2

Benign

0.054

T;T

Eigen

Benign

-0.90

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.51

T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.032

Sift

Benign

0.36

T;T

Sift4G

Benign

0.55

T;T

Polyphen

0.0020

B;.

Vest4

0.063

MutPred

0.47

Loss of ubiquitination at K22 (P = 0.0071);Loss of ubiquitination at K22 (P = 0.0071);

MVP

0.47

MPC

0.17

ClinPred

0.067

GERP RS

-11

Varity_R

0.38

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.026

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over