22-50714333-G-C

Variant names:

• chr22-50714333-G-C
• rs2106111
• NM_001372044.2:c.2321-584G>C

Variant summary

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

The NM_001372044.2(SHANK3):​c.2321-584G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 152,214 control chromosomes in the GnomAD database, including 35,849 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 0.67 (35849 hom., cov: 34)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.494
• Publications: 3 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.2321-584G>C		intron_variant	Intron 21 of 24	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2	c.2318-584G>C		intron_variant	Intron 19 of 22			ENSP00000510794.2

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102070 AN: 152096 Hom.: 35785 Cov.: 34

Gnomad AFR AF: 0.867

Gnomad AMI AF: 0.689

Gnomad AMR AF: 0.735

Gnomad ASJ AF: 0.603

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.651

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.671 AC: 102194 AN: 152214 Hom.: 35849 Cov.: 34 AF XY: 0.670 AC XY: 49876 AN XY: 74410

African (AFR) AF: 0.867 AC: 36031 AN: 41544

American (AMR) AF: 0.735 AC: 11255 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 2093 AN: 3470

East Asian (EAS) AF: 0.842 AC: 4365 AN: 5186

South Asian (SAS) AF: 0.665 AC: 3204 AN: 4820

European-Finnish (FIN) AF: 0.497 AC: 5257 AN: 10588

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.556 AC: 37781 AN: 67984

Other (OTH) AF: 0.656 AC: 1385 AN: 2112

Alfa AF: 0.610 Hom.: 3625

Bravo AF: 0.700

Asia WGS AF: 0.786 AC: 2735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.31
PhyloP100		0.49
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: rs2106111; hg19: chr22-51152761;