Genetic Variant SHANK3:p.Pro1716Ser (chr22-50731076-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001372044.2(SHANK3):c.5146C>T(p.Pro1716Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,336,346 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. 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. P1716T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.676

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: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
schizophrenia 15
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

SHANK3 links:

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ACMG classification

Classification was made for transcript

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=0.096274555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.5146C>T	p.Pro1716Ser	missense_variant	Exon 25 of 25	ENST00000710353.1	NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.2 link	c.5143C>T	p.Pro1715Ser	missense_variant	Exon 23 of 23			ENSP00000510794.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.48e-7

AC:

AN:

1336346

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

659470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27332

American (AMR)

AF:

0.00

AC:

AN:

32040

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22712

East Asian (EAS)

AF:

0.00

AC:

AN:

30050

South Asian (SAS)

AF:

0.00

AC:

AN:

76346

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

9.55e-7

AC:

AN:

1046784

Other (OTH)

AF:

0.00

AC:

AN:

54208

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.045

.;T

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-0.99

PhyloP100

0.68

PrimateAI

Uncertain

0.79

REVEL

Benign

0.063

Sift4G

Benign

0.16

T;T

Vest4

0.19

GERP RS

1.1

gMVP

0.29

Mutation Taster

=96/4

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over