Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001441024.1(SHANK2):c.3020A>G(p.Tyr1007Cys) 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_001441024.1 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.61

Publications

23 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 -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 VariationId is 130303.Status of the report is criteria_provided_single_submitter, 1 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2594 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441024.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHANK2	NM_012309.5	MANE Select	c.2900A>G	p.Tyr967Cys	missense	Exon 25 of 26	NP_036441.2
SHANK2	NM_001441024.1		c.3020A>G	p.Tyr1007Cys	missense	Exon 23 of 24	NP_001427953.1
SHANK2	NM_001441025.1		c.2849A>G	p.Tyr950Cys	missense	Exon 22 of 23	NP_001427954.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.2900A>G	p.Tyr967Cys	missense	Exon 25 of 26	ENSP00000469689.2
SHANK2	ENST00000409161.5	TSL:1	c.1112A>G	p.Tyr371Cys	missense	Exon 9 of 10	ENSP00000386491.1
SHANK2	ENST00000916035.1		c.2849A>G	p.Tyr950Cys	missense	Exon 22 of 23	ENSP00000586094.1

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

GnomAD2 exomes

AF:

0.0175

AC:

4409

AN:

251454

AF XY:

0.0177

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 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

African (AFR)

AF:

0.00373

AC:

125

AN:

33480

American (AMR)

AF:

0.0148

AC:

660

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0192

AC:

501

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00791

AC:

682

AN:

86258

European-Finnish (FIN)

AF:

0.0163

AC:

870

AN:

53382

Middle Eastern (MID)

AF:

0.0232

AC:

134

AN:

5768

European-Non Finnish (NFE)

AF:

0.0272

AC:

30248

AN:

1112008

Other (OTH)

AF:

0.0205

AC:

1240

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2485

4970

7455

9940

12425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1154

2308

3462

4616

5770

<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:

0.0170

AC:

2594

AN:

152260

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

1216

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00525

AC:

218

AN:

41554

American (AMR)

AF:

0.0173

AC:

264

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5174

South Asian (SAS)

AF:

0.00642

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0186

AC:

197

AN:

10608

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0258

AC:

1755

AN:

68008

Other (OTH)

AF:

0.0204

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0228

Hom.:

127

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

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.88

PhyloP100

3.6

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.22

Sift

Benign

0.043

Sift4G

Uncertain

0.059

Polyphen

1.0

Vest4

0.52

MPC

1.0

ClinPred

0.015

GERP RS

3.7

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.49

Mutation Taster

=98/2

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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rs62622853

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over