22-50720865-G-T

Variant names:

Variant summary

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

The NM_001372044.2(SHANK3):c.3218G>T(p.Gly1073Val) variant causes a missense change. The variant allele was found at a frequency of 0.000827 in 1,374,150 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1073A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00060 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 1 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 6.26

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: 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007617742).

BP6

Variant 22-50720865-G-T is Benign according to our data. Variant chr22-50720865-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 587798.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0006 (90/149918) while in subpopulation NFE AF = 0.00109 (73/67214). AF 95% confidence interval is 0.000886. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 90 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.3218G>T	p.Gly1073Val	missense	Exon 24 of 25	NP_001358973.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHANK3	ENST00000692848.2		c.3215G>T	p.Gly1072Val	missense	Exon 22 of 23	ENSP00000510794.2
SHANK3	ENST00000262795.8	TSL:5	c.2633G>T	p.Gly878Val	missense	Exon 20 of 21	ENSP00000489147.3
SHANK3	ENST00000664402.3		c.1175G>T	p.Gly392Val	missense	Exon 5 of 6	ENSP00000499475.2

Frequencies

GnomAD3 genomes

AF:

0.000601

AC:

AN:

149810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000486

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000598

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000412

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.000976

GnomAD2 exomes

AF:

0.00105

AC:

AN:

22808

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.00287

Gnomad AMR exome

AF:

0.000253

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00198

Gnomad OTH exome

AF:

0.00269

GnomAD4 exome

AF:

0.000855

AC:

1047

AN:

1224232

Hom.:

Cov.:

AF XY:

0.000843

AC XY:

502

AN XY:

595206

show subpopulations

African (AFR)

AF:

0.000254

AC:

AN:

23642

American (AMR)

AF:

0.000457

AC:

AN:

13116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17552

East Asian (EAS)

AF:

0.00

AC:

AN:

26880

South Asian (SAS)

AF:

0.0000703

AC:

AN:

56874

European-Finnish (FIN)

AF:

0.000333

AC:

AN:

30022

Middle Eastern (MID)

AF:

0.00198

AC:

AN:

3528

European-Non Finnish (NFE)

AF:

0.000977

AC:

980

AN:

1002572

Other (OTH)

AF:

0.000679

AC:

AN:

50046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000600

AC:

AN:

149918

Hom.:

Cov.:

AF XY:

0.000533

AC XY:

AN XY:

73188

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41268

American (AMR)

AF:

0.000597

AC:

AN:

15072

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000412

AC:

AN:

9718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

67214

Other (OTH)

AF:

0.000965

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.00109

Hom.:

Bravo

AF:

0.000525

ExAC

AF:

0.000336

AC:

ClinVar

ClinVar submissions as Germline

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)

SHANK3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0076

MetaSVM

Uncertain

-0.14

PhyloP100

6.3

PrimateAI

Pathogenic

0.86

REVEL

Benign

0.28

Sift4G

Benign

0.12

Vest4

0.34

GERP RS

3.0

gMVP

0.19

Mutation Taster

=98/2

polymorphism

(source)

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

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