rs749130556

Positions:

chr22-50731076-C-A

Variant summary

Our verdict is Benign. Variant got -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. 9/13 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 212176.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr22-50731076-C-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 456 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2 linkuse as main transcript	c.5146C>A	p.Pro1716Thr	missense_variant	25/25	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7 linkuse as main transcript	c.4588C>A	p.Pro1530Thr	missense_variant	22/22	5		ENSP00000489147	P1

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

GnomAD3 exomes

AF:

0.00286

AC:

329

AN:

114982

Hom.:

AF XY:

0.00279

AC XY:

177

AN XY:

63388

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 SAS exome

AF:

0.000708

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

Gnomad4 AFR exome

AF:

0.000659

Gnomad4 AMR exome

AF:

0.00128

Gnomad4 ASJ exome

AF:

0.00150

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000629

Gnomad4 FIN exome

AF:

0.00601

Gnomad4 NFE exome

AF:

0.00423

Gnomad4 OTH exome

AF:

0.00295

GnomAD4 genome

AF:

0.00303

AC:

456

AN:

150438

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

215

AN XY:

73478

show subpopulations

Gnomad4 AFR

AF:

0.000749

Gnomad4 AMR

AF:

0.000661

Gnomad4 ASJ

AF:

0.00174

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00645

Gnomad4 NFE

AF:

0.00489

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.00414

Hom.:

Bravo

AF:

0.00237

ExAC

AF:

0.000787

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SHANK3: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2018	This variant is associated with the following publications: (PMID: 17173049, 17999366, 18615476) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 11, 2014

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2019

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

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.083

.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.074

MetaRNN

Benign

0.0066

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Pathogenic

0.80

REVEL

Benign

0.058

Sift4G

Benign

0.10

T;T

Vest4

0.25

GERP RS

1.1

gMVP

0.34

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over