rs5770820

Variant names:

• chr22-50712045-G-A
• rs5770820
• ENST00000692848.2:c.2317+407G>A

Variant summary

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

The ENST00000692848.2(SHANK3):​c.2317+407G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,150 control chromosomes in the GnomAD database, including 3,867 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 0.20 (3867 hom., cov: 33)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.90
• 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 (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.2320+407G>A		intron_variant	Intron 21 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.2317+407G>A		intron_variant	Intron 19 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30689 AN: 152032 Hom.: 3862 Cov.: 33

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.359

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.202 AC: 30716 AN: 152150 Hom.: 3867 Cov.: 33 AF XY: 0.210 AC XY: 15653 AN XY: 74364

African (AFR) AF: 0.0710 AC: 2950 AN: 41542

American (AMR) AF: 0.220 AC: 3359 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 589 AN: 3472

East Asian (EAS) AF: 0.487 AC: 2510 AN: 5152

South Asian (SAS) AF: 0.291 AC: 1402 AN: 4818

European-Finnish (FIN) AF: 0.359 AC: 3795 AN: 10582

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15491 AN: 67978

Other (OTH) AF: 0.188 AC: 396 AN: 2112

Alfa AF: 0.216 Hom.: 7092

Bravo AF: 0.186

Asia WGS AF: 0.344 AC: 1197 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	0.21
DANN	Benign	0.56
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5770820; hg19: chr22-51150473;