Genetic Variant NM_012309.5:c.2453G>A (chr11-70490374-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_012309.5(SHANK2):c.2453G>A(p.Arg818His) variant causes a missense change. The variant allele was found at a frequency of 0.00345 in 1,614,102 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 33 hom. )

Consequence

SHANK2
NM_012309.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.32

Publications

13 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007972866).

BP6

Variant 11-70490374-C-T is Benign according to our data. Variant chr11-70490374-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212174.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00385 (587/152302) while in subpopulation NFE AF = 0.00518 (352/68012). AF 95% confidence interval is 0.00473. There are 3 homozygotes in GnomAd4. There are 300 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 587 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.2453G>A	p.Arg818His	missense	Exon 23 of 26	NP_036441.2
SHANK2	NM_001441024.1		c.2594G>A	p.Arg865His	missense	Exon 22 of 24	NP_001427953.1
SHANK2	NM_001441025.1		c.2423G>A	p.Arg808His	missense	Exon 21 of 23	NP_001427954.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.2453G>A	p.Arg818His	missense	Exon 23 of 26	ENSP00000469689.2
SHANK2	ENST00000409161.5	TSL:1	c.665G>A	p.Arg222His	missense	Exon 7 of 10	ENSP00000386491.1
SHANK2	ENST00000449116.6	TSL:1	n.732G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

587

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0167

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00463

AC:

1163

AN:

251454

AF XY:

0.00447

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.00539

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00341

AC:

4985

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00351

AC XY:

2556

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33476

American (AMR)

AF:

0.00143

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00310

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0202

AC:

1078

AN:

53402

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00321

AC:

3574

AN:

1111942

Other (OTH)

AF:

0.00290

AC:

175

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

281

562

844

1125

1406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00385

AC:

587

AN:

152302

Hom.:

Cov.:

AF XY:

0.00403

AC XY:

300

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41558

American (AMR)

AF:

0.00163

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0167

AC:

177

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00518

AC:

352

AN:

68012

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

102

136

170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00481

Hom.:

Bravo

AF:

0.00237

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00373

AC:

ExAC

AF:

0.00480

AC:

583

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00338

EpiControl

AF:

0.00314

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autism (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0080

MetaSVM

Uncertain

-0.048

PhyloP100

5.3

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.6

REVEL

Benign

0.26

Sift

Uncertain

0.017

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.81

MVP

0.38

MPC

1.4

ClinPred

0.040

GERP RS

4.6

gMVP

0.64

Mutation Taster

=93/7

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

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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

Computational scores

Splicing

Publications

Other links and lift over