NM_198993.5:c.1045G>C

Variant names:

• chr17-39213081-C-G
• rs1454223919
• NM_198993.5:c.1045G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_198993.5(STAC2):​c.1045G>C​(p.Val349Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V349M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: STAC2 NM_198993.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.72
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.099891 (below the threshold of 3.09). Trascript score misZ: 0.30072 (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198993.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAC2	NM_198993.5	MANE Select	c.1045G>C	p.Val349Leu	missense	Exon 10 of 11	NP_945344.1	Q6ZMT1-1
	STAC2	NM_001351360.2		c.619G>C	p.Val207Leu	missense	Exon 10 of 11	NP_001338289.1	Q6ZMT1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STAC2	ENST00000333461.6	TSL:1 MANE Select	c.1045G>C	p.Val349Leu	missense	Exon 10 of 11	ENSP00000327509.5	Q6ZMT1-1
	STAC2	ENST00000584501.1	TSL:1	n.*396G>C		non_coding_transcript_exon	Exon 10 of 11	ENSP00000463299.1	J3QKZ0
	STAC2	ENST00000584501.1	TSL:1	n.*396G>C		3_prime_UTR	Exon 10 of 11	ENSP00000463299.1	J3QKZ0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.067	D
MutationAssessor	Benign	0.13	N
PhyloP100		6.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.59
Sift	Benign	0.10	T
Sift4G	Benign	0.082	T
Polyphen		0.99	D
Vest4		0.72
MutPred		0.66		Loss of MoRF binding (P = 0.1166)
MVP		0.78
MPC		0.56
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.63
gMVP		0.53

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

Other links and lift over

dbSNP: rs1454223919; hg19: chr17-37369334;