22-50700952-T-C

Position:

• chr22-50700952-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK3	NM_001372044.2	c.1798+2149T>C		intron_variant			NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000262795.7	c.1213+2149T>C		intron_variant		5		ENSP00000489147.3
SHANK3	ENST00000445220.7	c.265+2149T>C		intron_variant		5
SHANK3	ENST00000414786.7	n.1797+2149T>C		intron_variant		5

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

Gnomad4 AFR AF: 0.799

Gnomad4 AMR AF: 0.849

Gnomad4 ASJ AF: 0.828

Gnomad4 EAS AF: 0.646

Gnomad4 SAS AF: 0.777

Gnomad4 FIN AF: 0.840

Gnomad4 NFE AF: 0.804

Gnomad4 OTH AF: 0.794

Alfa AF: 0.802 Hom.: 59376

Bravo AF: 0.803

Asia WGS AF: 0.701 AC: 2440 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	3.7
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs2341010; hg19: chr22-51139380;