Genetic Variant STAC2:p.Gly401Asp (chr17-39212326-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198993.5(STAC2):c.1202G>A(p.Gly401Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,459,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

STAC2
NM_198993.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.18

Variant links:

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]

STAC2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAC2	NM_198993.5 link	c.1202G>A	p.Gly401Asp	missense_variant	Exon 11 of 11	ENST00000333461.6	NP_945344.1	Q6ZMT1-1D0IN09
STAC2	NM_001351360.2 link	c.776G>A	p.Gly259Asp	missense_variant	Exon 11 of 11		NP_001338289.1
STAC2	XM_017024580.2 link	c.1217G>A	p.Gly406Asp	missense_variant	Exon 11 of 11		XP_016880069.1
STAC2	XM_017024581.2 link	c.1052G>A	p.Gly351Asp	missense_variant	Exon 9 of 9		XP_016880070.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STAC2	ENST00000333461.6 link	c.1202G>A	p.Gly401Asp	missense_variant	Exon 11 of 11	1	NM_198993.5	ENSP00000327509.5	Q6ZMT1-1
STAC2	ENST00000584501.1 link	n.*553G>A		non_coding_transcript_exon_variant	Exon 11 of 11	1		ENSP00000463299.1	J3QKZ0
STAC2	ENST00000584501.1 link	n.*553G>A		3_prime_UTR_variant	Exon 11 of 11	1		ENSP00000463299.1	J3QKZ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000407

AC:

AN:

245480

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133070

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000911

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1459926

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726048

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:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1202G>A (p.G401D) alteration is located in exon 11 (coding exon 11) of the STAC2 gene. This alteration results from a G to A substitution at nucleotide position 1202, causing the glycine (G) at amino acid position 401 to be replaced by an aspartic acid (D). 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.91

MutPred

0.89

Loss of MoRF binding (P = 0.0277);

MVP

0.95

MPC

0.65

ClinPred

0.99

GERP RS

4.3

Varity_R

0.93

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over