rs2040487

Positions:

• chr22-50708587-A-G
• chr22-50708587-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001372044.2(SHANK3):​c.2296+2435A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 152,012 control chromosomes in the GnomAD database, including 13,125 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 0.41 (13125 hom., cov: 32)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452

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]

ACMG classification

Verdict is Benign. Variant got -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 = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK3	NM_001372044.2	c.2296+2435A>G		intron_variant		ENST00000710353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK3	ENST00000262795.7	c.1711+2435A>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62097 AN: 151894 Hom.: 13105 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.370

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

GnomAD4 genome AF: 0.409 AC: 62152 AN: 152012 Hom.: 13125 Cov.: 32 AF XY: 0.417 AC XY: 30951 AN XY: 74312

Gnomad4 AFR AF: 0.343

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.616

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.401

Gnomad4 OTH AF: 0.368

Alfa AF: 0.393 Hom.: 15727

Bravo AF: 0.410

Asia WGS AF: 0.494 AC: 1719 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	4.9
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs2040487; hg19: chr22-51147015;