rs1001469

Variant names:

• chr22-50700325-A-G
• rs1001469
• ENST00000692848.2:c.1795+1522A>G

Your query was ambiguous. Multiple possible variants found:

• chr22-50700325-A-G
• chr22-50700325-A-T

Variant summary

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

The ENST00000692848.2(SHANK3):​c.1795+1522A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.798 in 151,798 control chromosomes in the GnomAD database, including 48,414 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 0.80 (48414 hom., cov: 29)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.449
• Publications: 7 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1798+1522A>G		intron_variant	Intron 15 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.1795+1522A>G		intron_variant	Intron 13 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.798 AC: 121033 AN: 151680 Hom.: 48396 Cov.: 29

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.842

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.772

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.799

Gnomad OTH AF: 0.795

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

GnomAD4 genome AF: 0.798 AC: 121102 AN: 151798 Hom.: 48414 Cov.: 29 AF XY: 0.798 AC XY: 59138 AN XY: 74154

African (AFR) AF: 0.790 AC: 32685 AN: 41390

American (AMR) AF: 0.842 AC: 12854 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2857 AN: 3472

East Asian (EAS) AF: 0.644 AC: 3297 AN: 5116

South Asian (SAS) AF: 0.772 AC: 3679 AN: 4766

European-Finnish (FIN) AF: 0.832 AC: 8781 AN: 10552

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.799 AC: 54305 AN: 67934

Other (OTH) AF: 0.788 AC: 1659 AN: 2104

Alfa AF: 0.794 Hom.: 29029

Bravo AF: 0.797

Asia WGS AF: 0.698 AC: 2429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	7.5
DANN	Benign	0.53
PhyloP100		0.45
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: rs1001469; hg19: chr22-51138753;