rs749130556

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001372044.2(SHANK3):c.5146C>A(p.Pro1716Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,486,778 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 15 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.676

Publications

3 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006612271).

BP6

Variant 22-50731076-C-A is Benign according to our data. Variant chr22-50731076-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212176.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00303 (456/150438) while in subpopulation NFE AF = 0.00489 (329/67282). AF 95% confidence interval is 0.00445. There are 0 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 456 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. 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
	SHANK3	NM_001372044.2	MANE Select	c.5146C>A	p.Pro1716Thr	missense	Exon 25 of 25	NP_001358973.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHANK3	ENST00000692848.2		c.5143C>A	p.Pro1715Thr	missense	Exon 23 of 23	ENSP00000510794.2	A0A8I5KZC4
SHANK3	ENST00000262795.8	TSL:5	c.4561C>A	p.Pro1521Thr	missense	Exon 21 of 21	ENSP00000489147.3	A0A0U1RQS4
SHANK3	ENST00000664402.3		c.3103C>A	p.Pro1035Thr	missense	Exon 6 of 6	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes

AF:

0.00303

AC:

456

AN:

150332

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000752

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.000662

Gnomad ASJ

AF:

0.00174

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00645

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.00286

AC:

329

AN:

114982

AF XY:

0.00279

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00132

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00690

Gnomad NFE exome

AF:

0.00471

Gnomad OTH exome

AF:

0.00354

GnomAD4 exome

AF:

0.00374

AC:

4992

AN:

1336340

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

2410

AN XY:

659466

show subpopulations

African (AFR)

AF:

0.000659

AC:

AN:

27332

American (AMR)

AF:

0.00128

AC:

AN:

32040

Ashkenazi Jewish (ASJ)

AF:

0.00150

AC:

AN:

22712

East Asian (EAS)

AF:

0.00

AC:

AN:

30050

South Asian (SAS)

AF:

0.000629

AC:

AN:

76346

European-Finnish (FIN)

AF:

0.00601

AC:

250

AN:

41614

Middle Eastern (MID)

AF:

0.00152

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

0.00423

AC:

4433

AN:

1046778

Other (OTH)

AF:

0.00295

AC:

160

AN:

54208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

329

658

988

1317

1646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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:

0.00303

AC:

456

AN:

150438

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

215

AN XY:

73478

show subpopulations

African (AFR)

AF:

0.000749

AC:

AN:

41368

American (AMR)

AF:

0.000661

AC:

AN:

15136

Ashkenazi Jewish (ASJ)

AF:

0.00174

AC:

AN:

3440

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00645

AC:

AN:

9926

Middle Eastern (MID)

AF:

0.00345

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00489

AC:

329

AN:

67282

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

114

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00414

Hom.:

Bravo

AF:

0.00237

ExAC

AF:

0.000787

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

M_CAP

Benign

0.074

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.0

PhyloP100

0.68

PrimateAI

Pathogenic

0.80

REVEL

Benign

0.058

Sift4G

Benign

0.10

Vest4

0.25

GERP RS

1.1

gMVP

0.34

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over