rs6010060

Variant names:

• chr22-50708011-A-G
• rs6010060
• ENST00000692848.2:c.2293+1859A>G

Variant summary

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

The ENST00000692848.2(SHANK3):​c.2293+1859A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0638 in 151,810 control chromosomes in the GnomAD database, including 338 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 0.064 (338 hom., cov: 31)
• Consequence: SHANK3 ENST00000692848.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.413
• Publications: 2 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 (NFE) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.2296+1859A>G		intron_variant	Intron 20 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.2293+1859A>G		intron_variant	Intron 18 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9665 AN: 151692 Hom.: 337 Cov.: 31

Gnomad AFR AF: 0.0476

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0570

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0386

Gnomad SAS AF: 0.0597

Gnomad FIN AF: 0.0840

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.0603

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

GnomAD4 genome AF: 0.0638 AC: 9681 AN: 151810 Hom.: 338 Cov.: 31 AF XY: 0.0632 AC XY: 4689 AN XY: 74136

African (AFR) AF: 0.0479 AC: 1985 AN: 41442

American (AMR) AF: 0.0569 AC: 867 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.0386 AC: 200 AN: 5176

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4824

European-Finnish (FIN) AF: 0.0840 AC: 872 AN: 10378

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5124 AN: 67970

Other (OTH) AF: 0.0602 AC: 127 AN: 2110

Alfa AF: 0.0710 Hom.: 124

Bravo AF: 0.0618

Asia WGS AF: 0.0490 AC: 172 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	9.2
DANN	Benign	0.78
PhyloP100		0.41
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: rs6010060; hg19: chr22-51146439;