NM_012309.5:c.4991T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012309.5(SHANK2):c.4991T>C(p.Ile1664Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,603,872 control chromosomes in the GnomAD database, including 23 homozygotes. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I1664I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 22 hom. )

Consequence

SHANK2
NM_012309.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.62

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004924059).

BP6

Variant 11-70473428-A-G is Benign according to our data. Variant chr11-70473428-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00364 (554/152200) while in subpopulation NFE AF = 0.00544 (370/68006). AF 95% confidence interval is 0.00498. There are 1 homozygotes in GnomAd4. There are 279 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 554 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5 link	c.4991T>C	p.Ile1664Thr	missense_variant	Exon 26 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.4991T>C	p.Ile1664Thr	missense_variant	Exon 26 of 26	5	NM_012309.5	ENSP00000469689.2		Q9UPX8-3

Frequencies

GnomAD3 genomes

AF:

0.00364

AC:

554

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00970

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00544

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00394

AC:

951

AN:

241270

AF XY:

0.00422

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00976

Gnomad NFE exome

AF:

0.00588

Gnomad OTH exome

AF:

0.00346

GnomAD4 exome

AF:

0.00470

AC:

6825

AN:

1451672

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

3445

AN XY:

722488

show subpopulations

African (AFR)

AF:

0.000807

AC:

AN:

33474

American (AMR)

AF:

0.00166

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00228

AC:

197

AN:

86248

European-Finnish (FIN)

AF:

0.00947

AC:

411

AN:

43416

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00531

AC:

5907

AN:

1111896

Other (OTH)

AF:

0.00338

AC:

204

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

393

786

1179

1572

1965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

208

416

624

832

1040

<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:

0.00364

AC:

554

AN:

152200

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

279

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.000723

AC:

AN:

41504

American (AMR)

AF:

0.00170

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00970

AC:

103

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00544

AC:

370

AN:

68006

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00477

Hom.:

Bravo

AF:

0.00290

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00434

AC:

527

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00523

EpiControl

AF:

0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autism, susceptibility to, 17

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 06, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHANK2: BP4, BS2 -

not specified

Benign:1

Nov 13, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.0030

T;T;T;T;.

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;T;T;T;T

MetaRNN

Benign

0.0049

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

1.6

PrimateAI

Benign

0.37

PROVEAN

Benign

0.18

.;N;N;.;.

REVEL

Benign

0.23

Sift

Benign

0.40

.;T;T;.;.

Sift4G

Benign

0.77

T;T;T;T;T

Polyphen

0.0020

.;.;.;.;B

Vest4

0.17

MVP

0.39

MPC

0.59

ClinPred

0.013

GERP RS

4.8

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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