rs117843717

Positions:

chr11-70490374-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012309.5(SHANK2):c.2453G>A(p.Arg818His) variant causes a missense change. The variant allele was found at a frequency of 0.00345 in 1,614,102 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 33 hom. )

Consequence

SHANK2
NM_012309.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.32

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]

SHANK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007972866).

BP6

Variant 11-70490374-C-T is Benign according to our data. Variant chr11-70490374-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212174.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00385 (587/152302) while in subpopulation NFE AF= 0.00518 (352/68012). AF 95% confidence interval is 0.00473. There are 3 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 587 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK2	NM_012309.5 linkuse as main transcript	c.2453G>A	p.Arg818His	missense_variant	23/26	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6 linkuse as main transcript	c.2453G>A	p.Arg818His	missense_variant	23/26	5	NM_012309.5	ENSP00000469689	P1	Q9UPX8-3

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

587

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00463

AC:

1163

AN:

251454

Hom.:

AF XY:

0.00447

AC XY:

607

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.00539

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00341

AC:

4985

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00351

AC XY:

2556

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00310

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0202

Gnomad4 NFE exome

AF:

0.00321

Gnomad4 OTH exome

AF:

0.00290

GnomAD4 genome

AF:

0.00385

AC:

587

AN:

152302

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0167

Gnomad4 NFE

AF:

0.00518

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00464

Hom.:

Bravo

AF:

0.00237

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00373

AC:

ExAC

AF:

0.00480

AC:

583

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SHANK2: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 16, 2014

- -

Autism

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Genetics Laboratory, Facudade de Medicina de Sao Jose do Rio Preto

Jan 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

T;T;T;T;.;T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0080

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.048

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.6

.;N;D;.;.;N;.;N

REVEL

Benign

0.26

Sift

Uncertain

0.017

.;D;D;.;.;D;.;D

Sift4G

Uncertain

0.012

D;D;D;D;D;D;D;D

Polyphen

1.0, 1.0

.;.;.;.;D;.;.;D

Vest4

0.81

MVP

0.38

MPC

1.4

ClinPred

0.040

GERP RS

4.6

gMVP

0.64

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.

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