rs61729471

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000692848.2(SHANK3):c.2344G>A(p.Ala782Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,593,368 control chromosomes in the GnomAD database, including 1,114 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 73 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1041 hom. )

Consequence

SHANK3
ENST00000692848.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.14

Publications

10 publications found

Variant links:

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

SHANK3 Gene-Disease associations (from GenCC):

Phelan-McDermid syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
schizophrenia 15
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

SHANK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020890832).

BP6

Variant 22-50714943-G-A is Benign according to our data. Variant chr22-50714943-G-A is described in ClinVar as Benign. ClinVar VariationId is 167676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.2347G>A	p.Ala783Thr	missense_variant	Exon 22 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2 link	c.2344G>A	p.Ala782Thr	missense_variant	Exon 20 of 23			ENSP00000510794.2		A0A8I5KZC4

Frequencies

GnomAD3 genomes

AF:

0.0271

AC:

4120

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00587

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0307

Gnomad ASJ

AF:

0.0308

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.0762

Gnomad FIN

AF:

0.0380

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0351

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0336

AC:

7063

AN:

210022

AF XY:

0.0354

show subpopulations

Gnomad AFR exome

AF:

0.00604

Gnomad AMR exome

AF:

0.0309

Gnomad ASJ exome

AF:

0.0263

Gnomad EAS exome

AF:

0.000770

Gnomad FIN exome

AF:

0.0399

Gnomad NFE exome

AF:

0.0325

Gnomad OTH exome

AF:

0.0266

GnomAD4 exome

AF:

0.0343

AC:

49366

AN:

1441130

Hom.:

1041

Cov.:

AF XY:

0.0353

AC XY:

25233

AN XY:

715096

show subpopulations

African (AFR)

AF:

0.00513

AC:

170

AN:

33134

American (AMR)

AF:

0.0309

AC:

1291

AN:

41798

Ashkenazi Jewish (ASJ)

AF:

0.0264

AC:

680

AN:

25742

East Asian (EAS)

AF:

0.000465

AC:

AN:

38730

South Asian (SAS)

AF:

0.0715

AC:

5925

AN:

82860

European-Finnish (FIN)

AF:

0.0416

AC:

2089

AN:

50240

Middle Eastern (MID)

AF:

0.0115

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.0338

AC:

37293

AN:

1103370

Other (OTH)

AF:

0.0308

AC:

1835

AN:

59626

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

2682

5365

8047

10730

13412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1398

2796

4194

5592

6990

<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

AF:

0.0270

AC:

4117

AN:

152238

Hom.:

Cov.:

AF XY:

0.0276

AC XY:

2054

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00585

AC:

243

AN:

41530

American (AMR)

AF:

0.0306

AC:

469

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0308

AC:

107

AN:

3470

East Asian (EAS)

AF:

0.00193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0758

AC:

366

AN:

4826

European-Finnish (FIN)

AF:

0.0380

AC:

404

AN:

10622

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0351

AC:

2389

AN:

67990

Other (OTH)

AF:

0.0194

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

210

420

631

841

1051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0309

Hom.:

262

Bravo

AF:

0.0236

TwinsUK

AF:

0.0356

AC:

132

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00717

AC:

ESP6500EA

AF:

0.0323

AC:

274

ExAC

AF:

0.0293

AC:

3510

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Aug 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Feb 16, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 28, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 14, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

.;T

Eigen

Benign

0.027

Eigen_PC

Benign

0.024

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0021

T;T

MetaSVM

Benign

-1.0

PhyloP100

3.1

PrimateAI

Uncertain

0.65

REVEL

Benign

0.10

Sift4G

Uncertain

0.032

D;D

Vest4

0.49

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.54

Mutation Taster

=95/5

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over