22-50713296-C-T

Variant names:

• chr22-50713296-C-T
• rs6010061
• NM_001372044.2:c.2321-1621C>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.2321-1621C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 151,916 control chromosomes in the GnomAD database, including 18,547 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 0.48 (18547 hom., cov: 33)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.473
• Publications: 6 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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.2321-1621C>T		intron_variant	Intron 21 of 24	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.2318-1621C>T		intron_variant	Intron 19 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.482 AC: 73106 AN: 151798 Hom.: 18518 Cov.: 33

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.576

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.428

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

GnomAD4 genome AF: 0.482 AC: 73192 AN: 151916 Hom.: 18547 Cov.: 33 AF XY: 0.497 AC XY: 36931 AN XY: 74248

African (AFR) AF: 0.516 AC: 21371 AN: 41406

American (AMR) AF: 0.547 AC: 8357 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 1251 AN: 3466

East Asian (EAS) AF: 0.877 AC: 4523 AN: 5160

South Asian (SAS) AF: 0.650 AC: 3133 AN: 4818

European-Finnish (FIN) AF: 0.576 AC: 6079 AN: 10558

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27078 AN: 67924

Other (OTH) AF: 0.427 AC: 902 AN: 2110

Alfa AF: 0.441 Hom.: 11750

Bravo AF: 0.479

Asia WGS AF: 0.685 AC: 2383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	8.8
DANN	Benign	0.81
PhyloP100		0.47
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: rs6010061; hg19: chr22-51151724;