dbSNP rs948195: SHANK2:c.2062-75270G>A (chr11-70578201-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012309.5(SHANK2):c.2062-75270G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 152,128 control chromosomes in the GnomAD database, including 48,287 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.79 ( 48287 hom., cov: 32)

Consequence

SHANK2
NM_012309.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.503

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.881 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5 link	c.2062-75270G>A		intron_variant	Intron 17 of 25	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.2062-75270G>A		intron_variant	Intron 17 of 25	5	NM_012309.5	ENSP00000469689.2		Q9UPX8-3

Frequencies

GnomAD3 genomes

AF:

0.795

AC:

120815

AN:

152010

Hom.:

48243

Cov.:

show subpopulations

Gnomad AFR

AF:

0.736

Gnomad AMI

AF:

0.849

Gnomad AMR

AF:

0.846

Gnomad ASJ

AF:

0.780

Gnomad EAS

AF:

0.778

Gnomad SAS

AF:

0.903

Gnomad FIN

AF:

0.893

Gnomad MID

AF:

0.864

Gnomad NFE

AF:

0.797

Gnomad OTH

AF:

0.796

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.795

AC:

120915

AN:

152128

Hom.:

48287

Cov.:

AF XY:

0.801

AC XY:

59539

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.736

AC:

30547

AN:

41496

American (AMR)

AF:

0.846

AC:

12944

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.780

AC:

2706

AN:

3470

East Asian (EAS)

AF:

0.778

AC:

4017

AN:

5164

South Asian (SAS)

AF:

0.904

AC:

4348

AN:

4812

European-Finnish (FIN)

AF:

0.893

AC:

9440

AN:

10574

Middle Eastern (MID)

AF:

0.861

AC:

253

AN:

294

European-Non Finnish (NFE)

AF:

0.797

AC:

54200

AN:

67990

Other (OTH)

AF:

0.798

AC:

1686

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1266

2533

3799

5066

6332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.798

Hom.:

25632

Bravo

AF:

0.788

Asia WGS

AF:

0.806

AC:

2803

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.060

(source)

DANN

Benign

0.53

PhyloP100

-0.50

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over