17-39213076-C-G

Variant names:

• chr17-39213076-C-G
• rs1441214058
• NM_198993.5:c.1050G>C

Variant summary

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

The NM_198993.5(STAC2):​c.1050G>C​(p.Arg350Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: STAC2 NM_198993.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.567

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STAC2	NM_198993.5	c.1050G>C	p.Arg350Ser	missense_variant	Exon 10 of 11	ENST00000333461.6	NP_945344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STAC2	ENST00000333461.6	c.1050G>C	p.Arg350Ser	missense_variant	Exon 10 of 11	1	NM_198993.5	ENSP00000327509.5
STAC2	ENST00000584501.1	n.*401G>C		non_coding_transcript_exon_variant	Exon 10 of 11	1		ENSP00000463299.1
STAC2	ENST00000584501.1	n.*401G>C		3_prime_UTR_variant	Exon 10 of 11	1		ENSP00000463299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461068 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726842

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: 0.0000261

Gnomad4 OTH exome AF: 0.00

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 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1050G>C (p.R350S) alteration is located in exon 10 (coding exon 10) of the STAC2 gene. This alteration results from a G to C substitution at nucleotide position 1050, causing the arginine (R) at amino acid position 350 to be replaced by a serine (S). 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	0.97
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.49	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.44		Loss of MoRF binding (P = 0.0514);
MVP		0.72
MPC		0.60
ClinPred		0.95	D
GERP RS		0.058
Varity_R		0.93
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1441214058; hg19: chr17-37369329;