22-50674600-TTCCCCGGCGCGAGCGGCCCCGGCCCGG-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_001372044.2(SHANK3):​c.185_211delTCCCCGGCGCGAGCGGCCCCGGCCCGG​(p.Phe62_Gly71delinsCys) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 28)

Consequence

SHANK3
NM_001372044.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.11
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_001372044.2.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SHANK3NM_001372044.2 linkc.185_211delTCCCCGGCGCGAGCGGCCCCGGCCCGG p.Phe62_Gly71delinsCys disruptive_inframe_deletion Exon 3 of 25 NP_001358973.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SHANK3ENST00000692848 linkc.-41_-15delTCCCCGGCGCGAGCGGCCCCGGCCCGG 5_prime_UTR_variant Exon 1 of 10 ENSP00000510794.2 A0A8I5KZC4
SHANK3ENST00000414786.7 linkn.187_213delTCCCCGGCGCGAGCGGCCCCGGCCCGG non_coding_transcript_exon_variant Exon 1 of 23 5
SHANK3ENST00000673971.2 linkn.-41_-15delTCCCCGGCGCGAGCGGCCCCGGCCCGG non_coding_transcript_exon_variant Exon 1 of 23 ENSP00000501192.2 A0A669KBA8
SHANK3ENST00000673971.2 linkn.-41_-15delTCCCCGGCGCGAGCGGCCCCGGCCCGG 5_prime_UTR_variant Exon 1 of 23 ENSP00000501192.2 A0A669KBA8

Frequencies

GnomAD3 genomes
Cov.:
28
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
28

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Phelan-McDermid syndrome Uncertain:1
Sep 16, 2024
Diagnostics Centre, Carl Von Ossietzky University Oldenburg
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The variant in the exon 3 causes a change in protein length as a result of an in-frame deletion/insertion at nucleotide position 182 to 211. This change causes a deletion of the amino acid phenylalanine at position 62 to glycine at position 71 and an insertion of a cysteine. This variant is classified as very rare since it is absent in gnomAD v4.1.0. Segregation of the parents revealed a de novo occurrence in the patient. In summary, the variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-51113028; API