rs41281537

chr22-50733239-G-A

Variant summary

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

The 22-50733239-G-A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 151,910 control chromosomes in the GnomAD database, including 110 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 0.028 (110 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHANK3 NM_001372044.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.768

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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.134 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHANK3	NM_001372044.2			downstream_gene_variant		ENST00000710353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHANK3	ENST00000262795.7			downstream_gene_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.0283 AC: 4296 AN: 151800 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.0574

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.0272

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0240

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0283 AC: 4300 AN: 151910 Hom.: 110 Cov.: 32 AF XY: 0.0292 AC XY: 2164 AN XY: 74212

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.0293

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.0593

Gnomad4 FIN AF: 0.0272

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.0238

Alfa AF: 0.0234 Hom.: 7

Bravo AF: 0.0290

Asia WGS AF: 0.0900 AC: 313 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.0
Dann	Benign	0.85

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41281537; hg19: chr22-51171667;