11-70820660-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_012309.5(SHANK2):c.1197G>A(p.Ala399Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 696,650 control chromosomes in the GnomAD database, including 12,270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2328 hom., cov: 33)

Exomes 𝑓: 0.18 ( 9942 hom. )

Consequence

SHANK2
NM_012309.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: -0.373

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autism, susceptibility to, 17
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

SHANK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 11-70820660-C-T is Benign according to our data. Variant chr11-70820660-C-T is described in ClinVar as Benign. ClinVar VariationId is 437876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.373 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5 link	c.1197G>A	p.Ala399Ala	synonymous_variant	Exon 12 of 26	ENST00000601538.6	NP_036441.2	Q9UPX8-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6 link	c.1197G>A	p.Ala399Ala	synonymous_variant	Exon 12 of 26	5	NM_012309.5	ENSP00000469689.2		Q9UPX8-3

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

23143

AN:

152058

Hom.:

2327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0406

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.193

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0776

Gnomad SAS

AF:

0.0473

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.155

GnomAD2 exomes

AF:

0.170

AC:

22433

AN:

131582

AF XY:

0.163

show subpopulations

Gnomad AFR exome

AF:

0.0327

Gnomad AMR exome

AF:

0.237

Gnomad ASJ exome

AF:

0.144

Gnomad EAS exome

AF:

0.0781

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.216

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.178

AC:

96698

AN:

544474

Hom.:

9942

Cov.:

AF XY:

0.171

AC XY:

49866

AN XY:

292360

show subpopulations

African (AFR)

AF:

0.0400

AC:

608

AN:

15186

American (AMR)

AF:

0.229

AC:

7547

AN:

32966

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

2545

AN:

18832

East Asian (EAS)

AF:

0.0634

AC:

2014

AN:

31760

South Asian (SAS)

AF:

0.0495

AC:

2986

AN:

60298

European-Finnish (FIN)

AF:

0.220

AC:

9936

AN:

45202

Middle Eastern (MID)

AF:

0.104

AC:

413

AN:

3984

European-Non Finnish (NFE)

AF:

0.214

AC:

65614

AN:

306506

Other (OTH)

AF:

0.169

AC:

5035

AN:

29740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

4507

9014

13521

18028

22535

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

300

600

900

1200

1500

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.152

AC:

23142

AN:

152176

Hom.:

2328

Cov.:

AF XY:

0.150

AC XY:

11162

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0405

AC:

1683

AN:

41566

American (AMR)

AF:

0.192

AC:

2944

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

447

AN:

3468

East Asian (EAS)

AF:

0.0778

AC:

401

AN:

5154

South Asian (SAS)

AF:

0.0471

AC:

227

AN:

4820

European-Finnish (FIN)

AF:

0.222

AC:

2352

AN:

10602

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.214

AC:

14532

AN:

67952

Other (OTH)

AF:

0.155

AC:

328

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

940

1880

2821

3761

4701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.190

Hom.:

4891

Bravo

AF:

0.149

Asia WGS

AF:

0.0760

AC:

264

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 27, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autism

Uncertain:1

Jan 01, 2016

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

6.4

(source)

DANN

Benign

0.96

PhyloP100

-0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over