dbSNP rs863223351: STAC2:p.Arg86Lys (chr17-39218007-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM2PP2PP5_ModerateBP4

The NM_198993.5(STAC2):c.257G>A(p.Arg86Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000216 in 1,385,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

STAC2
NM_198993.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.562

Publications

1 publications found

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]

STAC2 links:

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ACMG classification

Classification was made for transcript

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).

PP5

Variant 17-39218007-C-T is Pathogenic according to our data. Variant chr17-39218007-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208390.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.056702405). . Strength limited to SUPPORTING due to the PP5.

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.257G>A	p.Arg86Lys	missense	Exon 2 of 11	NP_945344.1	Q6ZMT1-1
	STAC2	NM_001351360.2		c.-30+62G>A		intron	N/A	NP_001338289.1	Q6ZMT1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAC2	ENST00000333461.6	TSL:1 MANE Select	c.257G>A	p.Arg86Lys	missense	Exon 2 of 11	ENSP00000327509.5	Q6ZMT1-1
STAC2	ENST00000584501.1	TSL:1	n.195+62G>A		intron	N/A	ENSP00000463299.1	J3QKZ0
STAC2	ENST00000945426.1		c.257G>A	p.Arg86Lys	missense	Exon 2 of 12	ENSP00000615485.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000216

AC:

AN:

1385874

Hom.:

Cov.:

AF XY:

0.00000437

AC XY:

AN XY:

686330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31904

American (AMR)

AF:

0.00

AC:

AN:

39588

Ashkenazi Jewish (ASJ)

AF:

0.0000413

AC:

AN:

24220

East Asian (EAS)

AF:

0.00

AC:

AN:

35648

South Asian (SAS)

AF:

0.00

AC:

AN:

82032

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4144

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1067874

Other (OTH)

AF:

0.0000177

AC:

AN:

56496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Childhood-onset schizophrenia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.7

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.016

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.45

M_CAP

Benign

0.026

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.56

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.28

REVEL

Benign

0.089

Sift

Benign

0.17

Sift4G

Benign

0.93

Polyphen

0.011

Vest4

0.15

MutPred

0.18

Gain of ubiquitination at R86 (P = 0.0109)

MVP

0.59

MPC

0.12

ClinPred

0.80

GERP RS

-1.9

Varity_R

0.068

gMVP

0.26

Mutation Taster

=96/4

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over