NM_182521.3:c.977T>A

Variant names:

• chr2-186829845-A-T
• rs1163456469
• NM_182521.3:c.977T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182521.3(ZSWIM2):​c.977T>A​(p.Leu326Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,432 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. L326P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZSWIM2 NM_182521.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.27
• Publications: 0 publications found

Genes affected

ZSWIM2 (HGNC:30990): (zinc finger SWIM-type containing 2) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in apoptotic process and protein polyubiquitination. Predicted to act upstream of or within positive regulation of extrinsic apoptotic signaling pathway via death domain receptors. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182521.3. 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
	ZSWIM2	NM_182521.3	MANE Select	c.977T>A	p.Leu326Gln	missense	Exon 8 of 9	NP_872327.2	Q8NEG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZSWIM2	ENST00000295131.3	TSL:1 MANE Select	c.977T>A	p.Leu326Gln	missense	Exon 8 of 9	ENSP00000295131.2	Q8NEG5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461432 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727014

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111756

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.70		Gain of solvent accessibility (P = 0.0789)
MVP		0.47
MPC		0.065
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.51
gMVP		0.75
Mutation Taster		=74/26	polymorphism

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: rs1163456469; hg19: chr2-187694572;