ENST00000692848:c.-220T>C

Variant names:

• chr22-50674422-T-C
• rs1359731523
• NM_001372044.2:c.8T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000692848.2(SHANK3):​c.8T>C​(p.Leu3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000065 (0 hom., cov: 20)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SHANK3 ENST00000692848.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.859
• Publications: 0 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)

ENSG00000301328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692848.2. 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.8T>C	p.Leu3Pro	missense	Exon 2 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.8T>C	p.Leu3Pro	missense	Exon 1 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.8T>C		non_coding_transcript_exon	Exon 1 of 22
	SHANK3	ENST00000673971.3		n.8T>C		non_coding_transcript_exon	Exon 1 of 23	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes AF: 0.0000653 AC: 8 AN: 122602 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000861

Gnomad OTH AF: 0.00117

GnomAD4 exome AF: 0.000175 AC: 2 AN: 11402 Hom.: 0 Cov.: 0 AF XY: 0.000236 AC XY: 2 AN XY: 8462

African (AFR) AF: 0.00 AC: 0 AN: 136

American (AMR) AF: 0.00 AC: 0 AN: 142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 102

East Asian (EAS) AF: 0.00 AC: 0 AN: 434

South Asian (SAS) AF: 0.00 AC: 0 AN: 1018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 52

European-Non Finnish (NFE) AF: 0.000220 AC: 2 AN: 9072

Other (OTH) AF: 0.00 AC: 0 AN: 344

GnomAD4 genome AF: 0.0000652 AC: 8 AN: 122652 Hom.: 0 Cov.: 20 AF XY: 0.000119 AC XY: 7 AN XY: 59030

African (AFR) AF: 0.00 AC: 0 AN: 32594

American (AMR) AF: 0.00 AC: 0 AN: 12432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3124

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.000290 AC: 1 AN: 3454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.0000861 AC: 5 AN: 58078

Other (OTH) AF: 0.00116 AC: 2 AN: 1720

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.56
PhyloP100		-0.86
PromoterAI		0.014	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1359731523; hg19: chr22-51112850;