rs9616915

Variant names:

• chr22-50679152-T-C
• rs9616915
• ENST00000692848.2:c.959T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000692848.2(SHANK3):​c.959T>C​(p.Ile320Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,565,054 control chromosomes in the GnomAD database, including 190,220 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16776 hom., cov: 33)
  • Exomes 𝑓: 0.49 (173444 hom.)
• Consequence: SHANK3 ENST00000692848.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.60
• Publications: 45 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=5.902149E-5).
• BP6: Variant 22-50679152-T-C is Benign according to our data. Variant chr22-50679152-T-C is described in ClinVar as Benign. ClinVar VariationId is 403431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.959T>C	p.Ile320Thr	missense_variant	Exon 8 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.959T>C	p.Ile320Thr	missense_variant	Exon 7 of 23			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69803 AN: 151812 Hom.: 16779 Cov.: 33

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.402

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.0871

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.487

GnomAD2 exomes AF: 0.427 AC: 88115 AN: 206444 AF XY: 0.434

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.297

Gnomad ASJ exome AF: 0.641

Gnomad EAS exome AF: 0.0761

Gnomad FIN exome AF: 0.474

Gnomad NFE exome AF: 0.518

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.488 AC: 689732 AN: 1413124 Hom.: 173444 Cov.: 67 AF XY: 0.485 AC XY: 337604 AN XY: 696450

African (AFR) AF: 0.424 AC: 13838 AN: 32662

American (AMR) AF: 0.309 AC: 12472 AN: 40406

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 15146 AN: 23806

East Asian (EAS) AF: 0.142 AC: 5485 AN: 38616

South Asian (SAS) AF: 0.370 AC: 29615 AN: 80116

European-Finnish (FIN) AF: 0.477 AC: 23767 AN: 49846

Middle Eastern (MID) AF: 0.497 AC: 2778 AN: 5586

European-Non Finnish (NFE) AF: 0.515 AC: 558451 AN: 1083830

Other (OTH) AF: 0.484 AC: 28180 AN: 58256

GnomAD4 genome AF: 0.460 AC: 69823 AN: 151930 Hom.: 16776 Cov.: 33 AF XY: 0.451 AC XY: 33461 AN XY: 74266

African (AFR) AF: 0.422 AC: 17453 AN: 41386

American (AMR) AF: 0.401 AC: 6124 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2209 AN: 3472

East Asian (EAS) AF: 0.0873 AC: 452 AN: 5178

South Asian (SAS) AF: 0.342 AC: 1649 AN: 4820

European-Finnish (FIN) AF: 0.468 AC: 4944 AN: 10560

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35255 AN: 67940

Other (OTH) AF: 0.481 AC: 1012 AN: 2102

Alfa AF: 0.493 Hom.: 60575

Bravo AF: 0.451

TwinsUK AF: 0.520 AC: 1930

ALSPAC AF: 0.520 AC: 2004

ESP6500AA AF: 0.404 AC: 1655

ESP6500EA AF: 0.517 AC: 4315

ExAC AF: 0.417 AC: 49744

Asia WGS AF: 0.249 AC: 869 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 51% of total chromosomes in ExAC -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 31, 2018

GeneDx

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

- -

Phelan-McDermid syndrome Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Mar 23, 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	0.052
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.0077	.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.000059	T;T
MetaSVM	Benign	-0.94	T
PhyloP100		1.6
PrimateAI	Benign	0.39	T
REVEL	Benign	0.037
Sift4G	Benign	0.72	T;T
Vest4		0.047
GERP RS		4.7
gMVP		0.46
Mutation Taster		=99/1	polymorphism (auto)

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: rs9616915; hg19: chr22-51117580; COSMIC: COSV53184118;