rs756638

Variant names:

• chr22-50733265-G-A
• rs756638
• NM_001372044.2:c.*1953G>A

Variant summary

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

The NM_001372044.2(SHANK3):​c.*1953G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 151,782 control chromosomes in the GnomAD database, including 8,967 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 0.33 (8967 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.950
• Publications: 13 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.486 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.*1953G>A		downstream_gene_variant		ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.*1953G>A		downstream_gene_variant				ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49290 AN: 151660 Hom.: 8957 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.277

Gnomad OTH AF: 0.332

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.325 AC: 49340 AN: 151778 Hom.: 8967 Cov.: 32 AF XY: 0.320 AC XY: 23715 AN XY: 74146

African (AFR) AF: 0.492 AC: 20338 AN: 41364

American (AMR) AF: 0.263 AC: 4006 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 971 AN: 3466

East Asian (EAS) AF: 0.185 AC: 959 AN: 5170

South Asian (SAS) AF: 0.181 AC: 873 AN: 4814

European-Finnish (FIN) AF: 0.228 AC: 2394 AN: 10484

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.277 AC: 18825 AN: 67934

Other (OTH) AF: 0.335 AC: 704 AN: 2100

Alfa AF: 0.290 Hom.: 11264

Bravo AF: 0.337

Asia WGS AF: 0.248 AC: 863 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.52
DANN	Benign	0.48
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs756638; hg19: chr22-51171693;