chr17-39216857-T-A

Variant names:

• chr17-39216857-T-A
• rs1049227980
• NM_198993.5:c.539A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_198993.5(STAC2):​c.539A>T​(p.His180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,078 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H180R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STAC2 NM_198993.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.20
• 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 3 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).

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.539A>T	p.His180Leu	missense	Exon 4 of 11	NP_945344.1	Q6ZMT1-1
	STAC2	NM_001351360.2		c.113A>T	p.His38Leu	missense	Exon 4 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.539A>T	p.His180Leu	missense	Exon 4 of 11	ENSP00000327509.5	Q6ZMT1-1
	STAC2	ENST00000584501.1	TSL:1	n.337A>T		non_coding_transcript_exon	Exon 4 of 11	ENSP00000463299.1	J3QKZ0
	STAC2	ENST00000945426.1		c.539A>T	p.His180Leu	missense	Exon 4 of 12	ENSP00000615485.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452078 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721334

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 43072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25894

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 84270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107664

Other (OTH) AF: 0.00 AC: 0 AN: 59986

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.041	D
Polyphen		0.99	D
Vest4		0.42
MutPred		0.21		Loss of loop (P = 0.1242)
MVP		0.98
MPC		0.22
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.38

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

Other links and lift over

dbSNP: rs1049227980; hg19: chr17-37373110; COSMIC: COSV61065951;