rs62622853

Positions:

chr11-70487393-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_012309.5(SHANK2):c.2900A>G(p.Tyr967Cys) variant causes a missense change. The variant allele was found at a frequency of 0.023 in 1,614,110 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.017 ( 26 hom., cov: 32)

Exomes 𝑓: 0.024 ( 455 hom. )

Consequence

SHANK2
NM_012309.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.61

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:

SHANK2 (HGNC:):

SHANK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041798055).

BP6

Variant 11-70487393-T-C is Benign according to our data. Variant chr11-70487393-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130303.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-70487393-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.017 (2594/152260) while in subpopulation NFE AF= 0.0258 (1755/68008). AF 95% confidence interval is 0.0248. There are 26 homozygotes in gnomad4. There are 1216 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2594 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK2	NM_012309.5 linkuse as main transcript	c.2900A>G	p.Tyr967Cys	missense_variant	25/26	ENST00000601538.6	NP_036441.2	Q9UPX8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6 linkuse as main transcript	c.2900A>G	p.Tyr967Cys	missense_variant	25/26	5	NM_012309.5	ENSP00000469689.2		Q9UPX8-3

Frequencies

GnomAD3 genomes

AF:

0.0171

AC:

2598

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00526

Gnomad AMI

AF:

0.0208

Gnomad AMR

AF:

0.0173

Gnomad ASJ

AF:

0.0159

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0211

GnomAD3 exomes

AF:

0.0175

AC:

4409

AN:

251454

Hom.:

AF XY:

0.0177

AC XY:

2399

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00486

Gnomad AMR exome

AF:

0.0139

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00692

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0257

Gnomad OTH exome

AF:

0.0235

GnomAD4 exome

AF:

0.0236

AC:

34461

AN:

1461850

Hom.:

455

Cov.:

AF XY:

0.0234

AC XY:

17033

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00373

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.0192

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00791

Gnomad4 FIN exome

AF:

0.0163

Gnomad4 NFE exome

AF:

0.0272

Gnomad4 OTH exome

AF:

0.0205

GnomAD4 genome

AF:

0.0170

AC:

2594

AN:

152260

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1216

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00525

Gnomad4 AMR

AF:

0.0173

Gnomad4 ASJ

AF:

0.0159

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0204

Alfa

AF:

0.0237

Hom.:

Bravo

AF:

0.0174

TwinsUK

AF:

0.0237

AC:

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.00614

AC:

ESP6500EA

AF:

0.0275

AC:

236

ExAC

AF:

0.0178

AC:

2163

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0288

EpiControl

AF:

0.0267

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

T;T;T;T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.86

D;D;D;D;D

MetaRNN

Benign

0.0042

T;T;T;T;T

MetaSVM

Benign

-0.88

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

.;D;D;.;.

REVEL

Benign

0.22

Sift

Benign

0.043

.;D;D;.;.

Sift4G

Uncertain

0.059

T;T;T;T;T

Polyphen

1.0

.;.;.;.;D

Vest4

0.52

MPC

1.0

ClinPred

0.015

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.49

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