17-39214968-T-C

Variant names:

• chr17-39214968-T-C
• rs2046388530
• NM_198993.5:c.755A>G

Variant summary

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

The NM_198993.5(STAC2):​c.755A>G​(p.Glu252Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: STAC2 NM_198993.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

Genes affected

STAC2 (HGNC:23990): (SH3 and cysteine rich domain 2) This gene encodes a protein containing an SH3 domain and a zinc finger domain. The encoded protein has been shown to regulate calcium channel inactivation in a human cell line. Reduced expression of this gene has been observed in human heart failure. [provided by RefSeq, May 2017]

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=0.18659204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAC2	NM_198993.5	c.755A>G	p.Glu252Gly	missense_variant	Exon 6 of 11	ENST00000333461.6	NP_945344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAC2	ENST00000333461.6	c.755A>G	p.Glu252Gly	missense_variant	Exon 6 of 11	1	NM_198993.5	ENSP00000327509.5
STAC2	ENST00000584501.1	n.*106A>G		non_coding_transcript_exon_variant	Exon 6 of 11	1		ENSP00000463299.1
STAC2	ENST00000584501.1	n.*106A>G		3_prime_UTR_variant	Exon 6 of 11	1		ENSP00000463299.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.755A>G (p.E252G) alteration is located in exon 6 (coding exon 6) of the STAC2 gene. This alteration results from a A to G substitution at nucleotide position 755, causing the glutamic acid (E) at amino acid position 252 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	0.11
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.055
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.060	T
Sift4G	Benign	0.097	T
Polyphen		0.030	B
Vest4		0.39
MutPred		0.21		Loss of stability (P = 0.0786);
MVP		0.79
MPC		0.19
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.13
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs2046388530; hg19: chr17-37371221;