GeneBe

rs975668627

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001372044.2(SHANK3):​c.28_39delGCCGCCGCCGCC​(p.Ala10_Ala13del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 142,764 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000076 ( 0 hom., cov: 20)
Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SHANK3
NM_001372044.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.76

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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_001372044.2

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.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
SHANK3
NM_001372044.2
MANE Select
c.28_39delGCCGCCGCCGCCp.Ala10_Ala13del
conservative_inframe_deletion
Exon 2 of 25NP_001358973.1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
SHANK3
ENST00000692848.2
c.28_39delGCCGCCGCCGCCp.Ala10_Ala13del
conservative_inframe_deletion
Exon 1 of 23ENSP00000510794.2A0A8I5KZC4
SHANK3
ENST00000414786.8
TSL:5
n.28_39delGCCGCCGCCGCC
non_coding_transcript_exon
Exon 1 of 22
SHANK3
ENST00000673971.3
n.28_39delGCCGCCGCCGCC
non_coding_transcript_exon
Exon 1 of 23ENSP00000501192.2A0A669KBA8

Frequencies

GnomAD3 genomes
AF:
0.00000760
AC:
1
AN:
131644
Hom.:
0
Cov.:
20
show subpopulations
Gnomad AFR
AF:
0.0000279
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000899
AC:
1
AN:
11120
Hom.:
0
AF XY:
0.000122
AC XY:
1
AN XY:
8218
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
132
American (AMR)
AF:
0.00
AC:
0
AN:
136
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
96
East Asian (EAS)
AF:
0.00231
AC:
1
AN:
432
South Asian (SAS)
AF:
0.00
AC:
0
AN:
1006
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
100
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
52
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
8824
Other (OTH)
AF:
0.00
AC:
0
AN:
342
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
AF:
0.00000760
AC:
1
AN:
131644
Hom.:
0
Cov.:
20
AF XY:
0.00
AC XY:
0
AN XY:
63634
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000279
AC:
1
AN:
35782
American (AMR)
AF:
0.00
AC:
0
AN:
13484
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3242
East Asian (EAS)
AF:
0.00
AC:
0
AN:
4114
South Asian (SAS)
AF:
0.00
AC:
0
AN:
3898
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
7330
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
260
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
60960
Other (OTH)
AF:
0.00
AC:
0
AN:
1810
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.8
Mutation Taster
=299/1
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs975668627; hg19: chr22-51112856; API