rs2301584

Positions:

• chr22-50733069-G-A
• chr22-50733069-G-C

Variant summary

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

The NM_001372044.2(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 NM_001372044.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.371

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=-0.76).
• 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/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.*1757G>A		3_prime_UTR_variant	25/25	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7	c.*1757G>A		3_prime_UTR_variant	22/22	5		ENSP00000489147	P1

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

Gnomad4 AFR exome AF: 0.265

Gnomad4 ASJ exome AF: 0.500

Gnomad4 SAS exome AF: 0.291

Gnomad4 FIN exome AF: 0.341

Gnomad4 NFE exome AF: 0.156

Gnomad4 OTH exome AF: 0.209

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

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.218

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.229

Alfa AF: 0.173 Hom.: 2464

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

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: rs2301584; hg19: chr22-51171497; COSMIC: COSV53187450; COSMIC: COSV53187450;