rs739365

Variant names:

• chr22-50701888-C-T
• rs739365
• NM_001372044.2:c.1799-1972C>T

Variant summary

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

The NM_001372044.2(SHANK3):​c.1799-1972C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 151,902 control chromosomes in the GnomAD database, including 10,546 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 0.36 (10546 hom., cov: 32)
• Consequence: SHANK3 NM_001372044.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 5 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=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.648 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	NM_001372044.2	MANE Select	c.1799-1972C>T		intron	N/A	NP_001358973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.1796-1972C>T		intron	N/A	ENSP00000510794.2
	SHANK3	ENST00000262795.8	TSL:5	c.1214-1972C>T		intron	N/A	ENSP00000489147.3
	SHANK3	ENST00000414786.8	TSL:5	n.1798-1972C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54788 AN: 151784 Hom.: 10525 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.313

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

GnomAD4 genome AF: 0.361 AC: 54867 AN: 151902 Hom.: 10546 Cov.: 32 AF XY: 0.372 AC XY: 27622 AN XY: 74272

African (AFR) AF: 0.372 AC: 15409 AN: 41384

American (AMR) AF: 0.440 AC: 6722 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 640 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3443 AN: 5166

South Asian (SAS) AF: 0.401 AC: 1928 AN: 4812

European-Finnish (FIN) AF: 0.450 AC: 4746 AN: 10552

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20837 AN: 67938

Other (OTH) AF: 0.313 AC: 660 AN: 2106

Alfa AF: 0.324 Hom.: 27180

Bravo AF: 0.362

Asia WGS AF: 0.484 AC: 1682 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	0.75
DANN	Benign	0.67
PhyloP100		-1.2
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: rs739365; hg19: chr22-51140316;