chr22-50674700-A-G

Variant names:

• chr22-50674700-A-G
• NM_001372044.2:c.284A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001372044.2(SHANK3):​c.284A>G​(p.Gln95Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 954,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• schizophrenia 15

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000301328 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24968022).

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.284A>G	p.Gln95Arg	missense	Exon 3 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.284A>G	p.Gln95Arg	missense	Exon 2 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000414786.8	TSL:5	n.286A>G		non_coding_transcript_exon	Exon 1 of 22
	SHANK3	ENST00000673971.3		n.284A>G		non_coding_transcript_exon	Exon 2 of 23	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 954184 Hom.: 0 Cov.: 29 AF XY: 0.00000218 AC XY: 1 AN XY: 458698

African (AFR) AF: 0.00 AC: 0 AN: 18330

American (AMR) AF: 0.00 AC: 0 AN: 12920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10398

East Asian (EAS) AF: 0.00 AC: 0 AN: 6120

South Asian (SAS) AF: 0.0000256 AC: 1 AN: 39052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 825348

Other (OTH) AF: 0.00 AC: 0 AN: 32532

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.2
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.084
Sift4G	Uncertain	0.026	D
Vest4		0.18
MutPred		0.40		Loss of helix (P = 0.0041)
GERP RS		0.84
PromoterAI		-0.035	Neutral
gMVP		0.47
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

hg19: chr22-51113128;