Genetic Variant SHANK3:p.Arg25Leu (chr22-50675058-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001372044.2(SHANK3):c.299G>T(p.Arg100Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000144 in 1,387,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SHANK3
NM_001372044.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.00

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.42163533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.299G>T	p.Arg100Leu	missense_variant	Exon 4 of 25		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK3	ENST00000692848.1 link	c.74G>T	p.Arg25Leu	missense_variant	Exon 2 of 10			ENSP00000510794.2		A0A8I5KZC4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000745

AC:

AN:

134184

Hom.:

AF XY:

0.00

AC XY:

AN XY:

73314

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000446

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1387466

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684512

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.0000245

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.74G>T (p.R25L) alteration is located in exon 2 (coding exon 2) of the SHANK3 gene. This alteration results from a G to T substitution at nucleotide position 74, causing the arginine (R) at amino acid position 25 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.074

.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.42

T;T

MetaSVM

Benign

-0.92

PrimateAI

Pathogenic

0.85

REVEL

Benign

0.20

Sift4G

Uncertain

0.0030

D;D

Vest4

0.51

MutPred

0.63

Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over