20-23440475-A-G

Variant names:

• chr20-23440475-A-G
• NM_138283.1:c.208A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138283.1(CSTL1):​c.208A>G​(p.Ser70Gly) variant causes a missense 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CSTL1 NM_138283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.602

Genes affected

CSTL1 (HGNC:15958): (cystatin like 1) 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 the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located at the telomeric end of the cystatin locus and encodes a type 2 cystatin-like protein. The specific function of this protein has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16751704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTL1	NM_138283.1	c.208A>G	p.Ser70Gly	missense_variant	Exon 2 of 4	ENST00000347397.5	NP_612140.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTL1	ENST00000347397.5	c.208A>G	p.Ser70Gly	missense_variant	Exon 2 of 4	1	NM_138283.1	ENSP00000344907.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208A>G (p.S70G) alteration is located in exon 2 (coding exon 1) of the CSTL1 gene. This alteration results from a A to G substitution at nucleotide position 208, causing the serine (S) at amino acid position 70 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.016	.;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.42	T;T;.
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Benign	0.038
Sift	Benign	0.067	.;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.018	.;B;B
Vest4		0.18, 0.16
MutPred		0.73		.;Loss of stability (P = 0.0828);Loss of stability (P = 0.0828);
MVP		0.055
MPC		0.059
ClinPred		0.052	T
GERP RS		0.96
Varity_R		0.17
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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.

Other links and lift over

hg19: chr20-23421112;