22-50697269-TG-TGGGGGGG

Variant names:

• chr22-50697269-T-TGGGGGG
• rs745950788
• ENST00000692848.2:c.1530-295_1530-294insGGGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000692848.2(SHANK3):​c.1530-295_1530-294insGGGGGG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 106,312 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.94
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1528-285_1528-280dupGGGGGG		intron_variant	Intron 12 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.1530-295_1530-294insGGGGGG		intron_variant	Intron 11 of 22			ENSP00000510794.2
SHANK3	ENST00000262795.8	c.948-295_948-294insGGGGGG		intron_variant	Intron 9 of 20	5		ENSP00000489147.3
SHANK3	ENST00000414786.8	n.1532-295_1532-294insGGGGGG		intron_variant	Intron 10 of 21	5
SHANK3	ENST00000673971.3	n.1530-295_1530-294insGGGGGG		intron_variant	Intron 11 of 22			ENSP00000501192.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.0000282 AC: 3 AN: 106312 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 54056

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2914

American (AMR) AF: 0.00 AC: 0 AN: 3182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3926

East Asian (EAS) AF: 0.00 AC: 0 AN: 10680

South Asian (SAS) AF: 0.00 AC: 0 AN: 1774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 704

European-Non Finnish (NFE) AF: 0.0000302 AC: 2 AN: 66274

Other (OTH) AF: 0.000145 AC: 1 AN: 6916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745950788; hg19: chr22-51135697;