rs715586

Variant names:

• chr22-50724710-C-T
• rs715586
• NM_001372044.2:c.4790+2273C>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.4790+2273C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,336 control chromosomes in the GnomAD database, including 1,119 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 0.11 (1119 hom., cov: 34)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.913
• 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: 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 = 0.146 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.4790+2273C>T		intron	N/A	NP_001358973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.4787+2273C>T		intron	N/A	ENSP00000510794.2
	SHANK3	ENST00000262795.8	TSL:5	c.4205+2273C>T		intron	N/A	ENSP00000489147.3
	SHANK3	ENST00000664402.3		c.2747+2273C>T		intron	N/A	ENSP00000499475.2

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16652 AN: 152216 Hom.: 1117 Cov.: 34

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0946

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.0951

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.109 AC: 16664 AN: 152336 Hom.: 1119 Cov.: 34 AF XY: 0.107 AC XY: 7947 AN XY: 74486

African (AFR) AF: 0.0305 AC: 1267 AN: 41586

American (AMR) AF: 0.144 AC: 2203 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3472

East Asian (EAS) AF: 0.0950 AC: 492 AN: 5180

South Asian (SAS) AF: 0.127 AC: 611 AN: 4828

European-Finnish (FIN) AF: 0.0951 AC: 1010 AN: 10620

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10078 AN: 68028

Other (OTH) AF: 0.105 AC: 222 AN: 2114

Alfa AF: 0.134 Hom.: 2443

Bravo AF: 0.107

Asia WGS AF: 0.104 AC: 360 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	0.16
DANN	Benign	0.43
PhyloP100		-0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs715586; hg19: chr22-51163138;