Genetic Variant SHANK3:p.Gly42Ala (chr22-50674539-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001372044.2(SHANK3):c.125G>C(p.Gly42Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000866 in 115,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000087 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.61

Publications

0 publications found

Variant links:

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)

SHANK3 links:

ENSG00000301328 (HGNC:):

ENSG00000301328 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.125G>C	p.Gly42Ala	missense	Exon 2 of 25	NP_001358973.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHANK3	ENST00000692848.2		c.125G>C	p.Gly42Ala	missense	Exon 1 of 23	ENSP00000510794.2	A0A8I5KZC4
SHANK3	ENST00000414786.8	TSL:5	n.125G>C		non_coding_transcript_exon	Exon 1 of 22
SHANK3	ENST00000673971.3		n.125G>C		non_coding_transcript_exon	Exon 1 of 23	ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes

AF:

0.00000866

AC:

AN:

115442

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000184

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

146444

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

69806

African (AFR)

AF:

0.00

AC:

AN:

2702

American (AMR)

AF:

0.00

AC:

AN:

140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

876

East Asian (EAS)

AF:

0.00

AC:

AN:

576

South Asian (SAS)

AF:

0.00

AC:

AN:

3252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

328

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

133806

Other (OTH)

AF:

0.00

AC:

AN:

4714

GnomAD4 genome

AF:

0.00000866

AC:

AN:

115442

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

56078

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30612

American (AMR)

AF:

0.00

AC:

AN:

12342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2948

East Asian (EAS)

AF:

0.00

AC:

AN:

3592

South Asian (SAS)

AF:

0.00

AC:

AN:

3324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

186

European-Non Finnish (NFE)

AF:

0.0000184

AC:

AN:

54220

Other (OTH)

AF:

0.00

AC:

AN:

1560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-1.6

PromoterAI

0.091

Neutral

(source)

Mutation Taster

=293/7

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over