chr11-70485471-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_012309.5(SHANK2):​c.4822G>A​(p.Val1608Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

SHANK2
NM_012309.5 missense

Scores

18

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.233
Variant links:
Genes affected
SHANK2 (HGNC:14295): (SH3 and multiple ankyrin repeat domains 2) This gene encodes a protein that is a member of the Shank family of synaptic proteins that may function as molecular scaffolds in the postsynaptic density of excitatory synapses. Shank proteins contain multiple domains for protein-protein interaction, including ankyrin repeats, and an SH3 domain. This particular family member contains a PDZ domain, a consensus sequence for cortactin SH3 domain-binding peptides and a sterile alpha motif. The alternative splicing demonstrated in Shank genes has been suggested as a mechanism for regulating the molecular structure of Shank and the spectrum of Shank-interacting proteins in the postsynaptic densities of the adult and developing brain. Alterations in the encoded protein may be associated with susceptibility to autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02334249).
BP6
Variant 11-70485471-C-T is Benign according to our data. Variant chr11-70485471-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 436712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SHANK2NM_012309.5 linkuse as main transcriptc.4822G>A p.Val1608Ile missense_variant 25/26 ENST00000601538.6 NP_036441.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SHANK2ENST00000601538.6 linkuse as main transcriptc.4822G>A p.Val1608Ile missense_variant 25/265 NM_012309.5 ENSP00000469689 P1Q9UPX8-3

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251316
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000194
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000248
AC:
363
AN:
1461612
Hom.:
0
Cov.:
33
AF XY:
0.000254
AC XY:
185
AN XY:
727088
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.000301
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152310
Hom.:
0
Cov.:
32
AF XY:
0.0000671
AC XY:
5
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000245
Hom.:
0
Bravo
AF:
0.000147
ExAC
AF:
0.000115
AC:
14
EpiCase
AF:
0.000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024SHANK2: BP4 -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoOct 11, 2016- -
Autism, susceptibility to, 17 Benign:1
Likely benign, criteria provided, single submitterclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical CenterSep 27, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
6.1
DANN
Benign
0.78
DEOGEN2
Benign
0.018
T;T;T;T;.
Eigen
Benign
-0.91
Eigen_PC
Benign
-0.91
FATHMM_MKL
Benign
0.094
N
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.023
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.44
.;N;N;N;.
REVEL
Benign
0.034
Sift
Benign
0.38
.;T;T;D;.
Sift4G
Benign
0.40
T;T;T;T;T
Polyphen
0.11
.;.;.;.;B
Vest4
0.098
MVP
0.25
MPC
0.44
ClinPred
0.015
T
GERP RS
0.15
gMVP
0.18

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

LitVar

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

Other links and lift over

dbSNP: rs543988574; hg19: chr11-70331576; COSMIC: COSV53588375; COSMIC: COSV53588375; API