22-50675077-C-T

Variant names:

• chr22-50675077-C-T
• rs891780204
• NM_001372044.2:c.318C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP7 BS2

The NM_001372044.2(SHANK3):​c.318C>T​(p.Pro106Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000359 in 1,392,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P106P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.77
• 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.318C>T	p.Pro106Pro	synonymous	Exon 4 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.318C>T	p.Pro106Pro	synonymous	Exon 3 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.-265C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000262795.8	TSL:5	c.-265C>T		5_prime_UTR	Exon 1 of 21	ENSP00000489147.3	A0A0U1RQS4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000359 AC: 5 AN: 1392588 Hom.: 0 Cov.: 31 AF XY: 0.00000582 AC XY: 4 AN XY: 687078

African (AFR) AF: 0.00 AC: 0 AN: 31540

American (AMR) AF: 0.00 AC: 0 AN: 35780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35764

South Asian (SAS) AF: 0.00 AC: 0 AN: 79142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1079014

Other (OTH) AF: 0.00 AC: 0 AN: 57788

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.96
PhyloP100		-1.8
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs891780204; hg19: chr22-51113505;