22-50700952-T-C

Variant names:

• chr22-50700952-T-C
• rs2341010
• NM_001372044.2:c.1798+2149T>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.1798+2149T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 152,090 control chromosomes in the GnomAD database, including 49,290 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 0.80 (49290 hom., cov: 32)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.296
• 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.837 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.1798+2149T>C		intron	N/A	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.1795+2149T>C		intron	N/A	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.1213+2149T>C		intron	N/A	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000414786.8	TSL:5	n.1797+2149T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122206 AN: 151972 Hom.: 49258 Cov.: 32

Gnomad AFR AF: 0.799

Gnomad AMI AF: 0.830

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.777

Gnomad FIN AF: 0.840

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.804

Gnomad OTH AF: 0.800

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

GnomAD4 genome AF: 0.804 AC: 122289 AN: 152090 Hom.: 49290 Cov.: 32 AF XY: 0.804 AC XY: 59788 AN XY: 74358

African (AFR) AF: 0.799 AC: 33140 AN: 41476

American (AMR) AF: 0.849 AC: 12994 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2869 AN: 3466

East Asian (EAS) AF: 0.646 AC: 3332 AN: 5160

South Asian (SAS) AF: 0.777 AC: 3742 AN: 4818

European-Finnish (FIN) AF: 0.840 AC: 8899 AN: 10598

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.804 AC: 54647 AN: 67950

Other (OTH) AF: 0.794 AC: 1678 AN: 2114

Alfa AF: 0.804 Hom.: 163702

Bravo AF: 0.803

Asia WGS AF: 0.701 AC: 2440 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.7
DANN	Benign	0.31
PhyloP100		-0.30
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: rs2341010; hg19: chr22-51139380;