chr22-50733069-G-A

Variant names:

• chr22-50733069-G-A
• rs2301584
• ENST00000692848.2:c.*1757G>A

Variant summary

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

The ENST00000692848.2(SHANK3):​c.*1757G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 154,402 control chromosomes in the GnomAD database, including 4,555 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 0.23 (4482 hom., cov: 33)
  • Exomes 𝑓: 0.24 (73 hom.)
• Consequence: SHANK3 ENST00000692848.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.371
• 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=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.*1757G>A		3_prime_UTR_variant	Exon 25 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.*1757G>A		3_prime_UTR_variant	Exon 23 of 23			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35416 AN: 151840 Hom.: 4469 Cov.: 33

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.218

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.236 AC: 578 AN: 2448 Hom.: 73 Cov.: 0 AF XY: 0.245 AC XY: 310 AN XY: 1264

African (AFR) AF: 0.265 AC: 18 AN: 68

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.291 AC: 25 AN: 86

European-Finnish (FIN) AF: 0.341 AC: 142 AN: 416

Middle Eastern (MID) AF: 0.212 AC: 341 AN: 1608

European-Non Finnish (NFE) AF: 0.156 AC: 15 AN: 96

Other (OTH) AF: 0.209 AC: 36 AN: 172

GnomAD4 genome AF: 0.233 AC: 35465 AN: 151954 Hom.: 4482 Cov.: 33 AF XY: 0.238 AC XY: 17679 AN XY: 74276

African (AFR) AF: 0.332 AC: 13762 AN: 41458

American (AMR) AF: 0.218 AC: 3333 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3472

East Asian (EAS) AF: 0.203 AC: 1049 AN: 5178

South Asian (SAS) AF: 0.227 AC: 1087 AN: 4798

European-Finnish (FIN) AF: 0.305 AC: 3204 AN: 10504

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.172 AC: 11704 AN: 67962

Other (OTH) AF: 0.229 AC: 483 AN: 2110

Alfa AF: 0.186 Hom.: 4708

Bravo AF: 0.231

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.92
DANN	Benign	0.88
PhyloP100		-0.37
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: rs2301584; hg19: chr22-51171497; COSMIC: COSV53187450; COSMIC: COSV53187450;