chr22-50720882-G-A

Variant names:

• chr22-50720882-G-A
• rs13057681
• ENST00000692848.2:c.3232G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000692848.2(SHANK3):​c.3232G>A​(p.Asp1078Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000233 in 1,286,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: SHANK3 ENST00000692848.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.88
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20623901).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.3235G>A	p.Asp1079Asn	missense_variant	Exon 24 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.3232G>A	p.Asp1078Asn	missense_variant	Exon 22 of 23			ENSP00000510794.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000233 AC: 3 AN: 1286908 Hom.: 0 Cov.: 34 AF XY: 0.00000159 AC XY: 1 AN XY: 630354

African (AFR) AF: 0.00 AC: 0 AN: 25456

American (AMR) AF: 0.00 AC: 0 AN: 21476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20920

East Asian (EAS) AF: 0.00 AC: 0 AN: 29050

South Asian (SAS) AF: 0.00 AC: 0 AN: 66074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32058

Middle Eastern (MID) AF: 0.000252 AC: 1 AN: 3968

European-Non Finnish (NFE) AF: 0.00000193 AC: 2 AN: 1034638

Other (OTH) AF: 0.00 AC: 0 AN: 53268

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	.;T
Eigen	Benign	0.035
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.76	T
PhyloP100		8.9
PrimateAI	Pathogenic	0.90	D
REVEL	Benign	0.18
Sift4G	Uncertain	0.011	D;D
Vest4		0.18
GERP RS		4.2
gMVP		0.12
Mutation Taster		=92/8	polymorphism

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: rs13057681; hg19: chr22-51159310;