rs9616915

chr22-50679152-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001372044.2(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. 10/12 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 NM_001372044.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.60

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 403431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50679152-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
SHANK3	NM_001372044.2	c.959T>C	p.Ile320Thr	missense_variant	8/25	ENST00000710353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK3	ENST00000262795.7	c.377T>C	p.Ile126Thr	missense_variant	5/22	5		P1

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

GnomAD3 exomes AF: 0.427 AC: 88115 AN: 206444 Hom.: 20712 AF XY: 0.434 AC XY: 48506 AN XY: 111770

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 SAS exome AF: 0.373

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

Gnomad4 AFR exome AF: 0.424

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.636

Gnomad4 EAS exome AF: 0.142

Gnomad4 SAS exome AF: 0.370

Gnomad4 FIN exome AF: 0.477

Gnomad4 NFE exome AF: 0.515

Gnomad4 OTH exome AF: 0.484

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

Gnomad4 AFR AF: 0.422

Gnomad4 AMR AF: 0.401

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.0873

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.519

Gnomad4 OTH AF: 0.481

Alfa AF: 0.497 Hom.: 27185

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Phelan-McDermid syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2016

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Benign	0.94
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
MutationTaster	Benign	1.0	P;P
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

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

LitVar

Other links and lift over

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