chr22-50697269-T-TG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The ENST00000692848.2(SHANK3):c.1530-295_1530-294insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00892 in 240,746 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 2 hom., cov: 29)

Exomes 𝑓: 0.013 ( 2 hom. )

Consequence

SHANK3
ENST00000692848.2 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 2.94

Publications

1 publications found

Variant links:

Genes affected

SHANK3 (HGNC:14294): (SH3 and multiple ankyrin repeat domains 3) This gene is a member of the Shank gene family. Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in synapse formation and dendritic spine maturation. Mutations in this gene are a cause of autism spectrum disorder (ASD), which is characterized by impairments in social interaction and communication, and restricted behavioral patterns and interests. Mutations in this gene also cause schizophrenia type 15, and are a major causative factor in the neurological symptoms of 22q13.3 deletion syndrome, which is also known as Phelan-McDermid syndrome. Additional isoforms have been described for this gene but they have not yet been experimentally verified. [provided by RefSeq, Mar 2012]

SHANK3 Gene-Disease associations (from GenCC):

Phelan-McDermid syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
schizophrenia 15
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

SHANK3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 22-50697269-T-TG is Benign according to our data. Variant chr22-50697269-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 50948.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 = 0.00595 (801/134670) while in subpopulation NFE AF = 0.00839 (524/62482). AF 95% confidence interval is 0.00779. There are 2 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 801 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK3	NM_001372044.2 link	c.1528-280dupG		intron_variant	Intron 12 of 24		NP_001358973.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
SHANK3	ENST00000692848.2 link	c.1530-295_1530-294insG	intron_variant	Intron 11 of 22		ENSP00000510794.2	A0A8I5KZC4
SHANK3	ENST00000262795.8 link	c.948-295_948-294insG	intron_variant	Intron 9 of 20	5	ENSP00000489147.3	A0A0U1RQS4
SHANK3	ENST00000414786.8 link	n.1532-295_1532-294insG	intron_variant	Intron 10 of 21	5
SHANK3	ENST00000673971.3 link	n.1530-295_1530-294insG	intron_variant	Intron 11 of 22		ENSP00000501192.2	A0A669KBA8

Frequencies

GnomAD3 genomes

AF:

0.00596

AC:

802

AN:

134598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00774

Gnomad ASJ

AF:

0.00878

Gnomad EAS

AF:

0.000716

Gnomad SAS

AF:

0.00129

Gnomad FIN

AF:

0.00335

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00840

Gnomad OTH

AF:

0.00594

GnomAD2 exomes

AF:

0.00523

AC:

AN:

3636

AF XY:

0.00642

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00325

Gnomad NFE exome

AF:

0.00804

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0127

AC:

1346

AN:

106076

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

678

AN XY:

53930

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00549

AC:

AN:

2912

American (AMR)

AF:

0.00881

AC:

AN:

3178

Ashkenazi Jewish (ASJ)

AF:

0.0148

AC:

AN:

3910

East Asian (EAS)

AF:

0.000281

AC:

AN:

10680

South Asian (SAS)

AF:

0.00338

AC:

AN:

1774

European-Finnish (FIN)

AF:

0.0107

AC:

106

AN:

9912

Middle Eastern (MID)

AF:

0.00

AC:

AN:

704

European-Non Finnish (NFE)

AF:

0.0157

AC:

1040

AN:

66100

Other (OTH)

AF:

0.0129

AC:

AN:

6906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.377

Heterozygous variant carriers

102

153

204

255

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:

0.00595

AC:

801

AN:

134670

Hom.:

Cov.:

AF XY:

0.00548

AC XY:

359

AN XY:

65452

show subpopulations

African (AFR)

AF:

0.00269

AC:

AN:

36006

American (AMR)

AF:

0.00772

AC:

105

AN:

13594

Ashkenazi Jewish (ASJ)

AF:

0.00878

AC:

AN:

3190

East Asian (EAS)

AF:

0.000717

AC:

AN:

4182

South Asian (SAS)

AF:

0.00129

AC:

AN:

3886

European-Finnish (FIN)

AF:

0.00335

AC:

AN:

8358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00839

AC:

524

AN:

62482

Other (OTH)

AF:

0.00589

AC:

AN:

1868

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

107

143

179

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:

0.00120

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 13, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2018

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SHANK3: BS1 -

Jan 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Phelan-McDermid syndrome

Uncertain:1

Mar 01, 2013

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.9

Mutation Taster

=120/80

disease causing (fs/PTC)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over