22-50720741-G-C

Variant names:

• chr22-50720741-G-C
• rs530255181
• NM_001372044.2:c.3094G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001372044.2(SHANK3):​c.3094G>C​(p.Ala1032Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 146,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1032S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SHANK3 NM_001372044.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27781862).

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.3094G>C	p.Ala1032Pro	missense	Exon 24 of 25	NP_001358973.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK3	ENST00000692848.2		c.3091G>C	p.Ala1031Pro	missense	Exon 22 of 23	ENSP00000510794.2	A0A8I5KZC4
	SHANK3	ENST00000262795.8	TSL:5	c.2509G>C	p.Ala837Pro	missense	Exon 20 of 21	ENSP00000489147.3	A0A0U1RQS4
	SHANK3	ENST00000664402.3		c.1051G>C	p.Ala351Pro	missense	Exon 5 of 6	ENSP00000499475.2	A0A590UJL3

Frequencies

GnomAD3 genomes AF: 0.00000681 AC: 1 AN: 146788 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1083712 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 531678

African (AFR) AF: 0.00 AC: 0 AN: 19356

American (AMR) AF: 0.00 AC: 0 AN: 13608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13836

East Asian (EAS) AF: 0.00 AC: 0 AN: 11314

South Asian (SAS) AF: 0.00 AC: 0 AN: 60958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 902356

Other (OTH) AF: 0.00 AC: 0 AN: 39054

GnomAD4 genome AF: 0.00000681 AC: 1 AN: 146788 Hom.: 0 Cov.: 33 AF XY: 0.0000140 AC XY: 1 AN XY: 71438

African (AFR) AF: 0.00 AC: 0 AN: 40932

American (AMR) AF: 0.0000676 AC: 1 AN: 14782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65994

Other (OTH) AF: 0.00 AC: 0 AN: 2018

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
AlphaMissense	Benign	0.26
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0072	T
Eigen	Benign	0.016
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.33	T
PhyloP100		2.2
PrimateAI	Pathogenic	0.94	D
REVEL	Benign	0.23
Sift4G	Benign	0.46	T
Vest4		0.26
GERP RS		4.4
gMVP		0.18
Mutation Taster		=38/62	disease causing

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: rs530255181; hg19: chr22-51159169;