rs8137951

Variant names:

• chr22-50727236-G-A
• rs8137951
• ENST00000692848.2:c.4788-3485G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000692848.2(SHANK3):​c.4788-3485G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 151,846 control chromosomes in the GnomAD database, including 10,492 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10492 hom., cov: 32)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.220
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.4791-3485G>A		intron_variant	Intron 24 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.4788-3485G>A		intron_variant	Intron 22 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54749 AN: 151730 Hom.: 10467 Cov.: 32

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.350

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.295

Gnomad OTH AF: 0.347

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.361 AC: 54831 AN: 151846 Hom.: 10492 Cov.: 32 AF XY: 0.361 AC XY: 26796 AN XY: 74164

African (AFR) AF: 0.493 AC: 20429 AN: 41400

American (AMR) AF: 0.325 AC: 4953 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 748 AN: 3464

East Asian (EAS) AF: 0.430 AC: 2222 AN: 5164

South Asian (SAS) AF: 0.357 AC: 1719 AN: 4812

European-Finnish (FIN) AF: 0.350 AC: 3677 AN: 10512

Middle Eastern (MID) AF: 0.197 AC: 58 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20038 AN: 67932

Other (OTH) AF: 0.352 AC: 742 AN: 2106

Alfa AF: 0.321 Hom.: 6632

Bravo AF: 0.363

Asia WGS AF: 0.445 AC: 1545 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.69
DANN	Benign	0.39
PhyloP100		-0.22
Mutation Taster		=100/0	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: rs8137951; hg19: chr22-51165664;