chr11-70486994-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_012309.5(SHANK2):c.3299C>T(p.Pro1100Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,611,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SHANK2
NM_012309.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.05

Publications

3 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26787516).

BP6

Variant 11-70486994-G-A is Benign according to our data. Variant chr11-70486994-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 212161.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 13 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012309.5. 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.3299C>T	p.Pro1100Leu	missense	Exon 25 of 26	NP_036441.2
SHANK2	NM_001441024.1		c.3419C>T	p.Pro1140Leu	missense	Exon 23 of 24	NP_001427953.1
SHANK2	NM_001441025.1		c.3248C>T	p.Pro1083Leu	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.3299C>T	p.Pro1100Leu	missense	Exon 25 of 26	ENSP00000469689.2
SHANK2	ENST00000409161.5	TSL:1	c.1511C>T	p.Pro504Leu	missense	Exon 9 of 10	ENSP00000386491.1
SHANK2	ENST00000656230.1		c.2162C>T	p.Pro721Leu	missense	Exon 15 of 16	ENSP00000499561.1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000864

AC:

AN:

243104

AF XY:

0.0000826

show subpopulations

Gnomad AFR exome

AF:

0.000137

Gnomad AMR exome

AF:

0.0000871

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.000334

GnomAD4 exome

AF:

0.000112

AC:

164

AN:

1458824

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

725840

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.0000895

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50734

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000135

AC:

150

AN:

1111754

Other (OTH)

AF:

0.000116

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

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:

0.000122

Hom.:

Bravo

AF:

0.000110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.023

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.49

PhyloP100

5.1

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.15

Sift

Benign

0.030

Sift4G

Benign

0.30

Polyphen

1.0

Vest4

0.78

MVP

0.41

MPC

0.53

ClinPred

0.12

GERP RS

4.9

gMVP

0.70

Mutation Taster

=94/6

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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