22-50718505-A-G

Variant names:

• chr22-50718505-A-G
• rs6010063
• NM_001372044.2:c.2537-1679A>G

Variant summary

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

The NM_001372044.2(SHANK3):​c.2537-1679A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 152,088 control chromosomes in the GnomAD database, including 17,967 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 0.48 (17967 hom., cov: 33)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.429
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Laboratory for Molecular Medicine
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372044.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.2537-1679A>G		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.2534-1679A>G		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.1952-1679A>G		intron	N/A	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.494-1679A>G		intron	N/A	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes AF: 0.483 AC: 73332 AN: 151968 Hom.: 17931 Cov.: 33

Gnomad AFR AF: 0.541

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.462

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

GnomAD4 genome AF: 0.483 AC: 73427 AN: 152088 Hom.: 17967 Cov.: 33 AF XY: 0.480 AC XY: 35655 AN XY: 74348

African (AFR) AF: 0.541 AC: 22460 AN: 41480

American (AMR) AF: 0.476 AC: 7271 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1297 AN: 3470

East Asian (EAS) AF: 0.536 AC: 2773 AN: 5178

South Asian (SAS) AF: 0.482 AC: 2328 AN: 4828

European-Finnish (FIN) AF: 0.449 AC: 4749 AN: 10582

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.456 AC: 30966 AN: 67960

Other (OTH) AF: 0.468 AC: 987 AN: 2110

Alfa AF: 0.462 Hom.: 56383

Bravo AF: 0.484

Asia WGS AF: 0.562 AC: 1952 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	4.9
DANN	Benign	0.55
PhyloP100		0.43
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: rs6010063; hg19: chr22-51156933;