17-39212326-C-T

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

7
11
1

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]

Genome browser will be placed here

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
STAC2NM_198993.5 linkc.1202G>A p.Gly401Asp missense_variant Exon 11 of 11 ENST00000333461.6 NP_945344.1 Q6ZMT1-1D0IN09
STAC2NM_001351360.2 linkc.776G>A p.Gly259Asp missense_variant Exon 11 of 11 NP_001338289.1
STAC2XM_017024580.2 linkc.1217G>A p.Gly406Asp missense_variant Exon 11 of 11 XP_016880069.1
STAC2XM_017024581.2 linkc.1052G>A p.Gly351Asp missense_variant Exon 9 of 9 XP_016880070.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STAC2ENST00000333461.6 linkc.1202G>A p.Gly401Asp missense_variant Exon 11 of 11 1 NM_198993.5 ENSP00000327509.5 Q6ZMT1-1
STAC2ENST00000584501.1 linkn.*553G>A non_coding_transcript_exon_variant Exon 11 of 11 1 ENSP00000463299.1 J3QKZ0
STAC2ENST00000584501.1 linkn.*553G>A 3_prime_UTR_variant Exon 11 of 11 1 ENSP00000463299.1 J3QKZ0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000407
AC:
1
AN:
245480
Hom.:
0
AF XY:
0.00000751
AC XY:
1
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:
9
AN:
1459926
Hom.:
0
Cov.:
31
AF XY:
0.00000689
AC XY:
5
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.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

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
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.96
D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
0.68
D
MutationAssessor
Uncertain
2.5
M
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.89
Loss of MoRF binding (P = 0.0277);
MVP
0.95
MPC
0.65
ClinPred
0.99
D
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.

Other links and lift over

dbSNP: rs767812919; hg19: chr17-37368579; API