rs2040487

Variant names:

• chr22-50708587-A-G
• rs2040487
• NM_001372044.2:c.2296+2435A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine
• 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 = 0.598 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.2296+2435A>G		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.2293+2435A>G		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.1711+2435A>G		intron	N/A	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.253+2435A>G		intron	N/A	ENSP00000499475.2	A0A590UJL3

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

African (AFR) AF: 0.343 AC: 14230 AN: 41460

American (AMR) AF: 0.516 AC: 7874 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1119 AN: 3466

East Asian (EAS) AF: 0.616 AC: 3185 AN: 5172

South Asian (SAS) AF: 0.473 AC: 2282 AN: 4822

European-Finnish (FIN) AF: 0.472 AC: 4980 AN: 10562

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.401 AC: 27230 AN: 67950

Other (OTH) AF: 0.368 AC: 775 AN: 2108

Alfa AF: 0.395 Hom.: 20313

Bravo AF: 0.410

Asia WGS AF: 0.494 AC: 1719 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.9
DANN	Benign	0.42
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: rs2040487; hg19: chr22-51147015;