Genetic Variant SHANK2:p.Leu1387_Pro1388dup (chr11-70486126-G-GAATGGC) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_001441024.1(SHANK2):c.4281_4286dupGCCATT(p.Leu1427_Pro1428dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00161 in 1,614,024 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 1 hom. )

Consequence

SHANK2
NM_001441024.1 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 6.81

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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001441024.1.

BP6

Variant 11-70486126-G-GAATGGC is Benign according to our data. Variant chr11-70486126-G-GAATGGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436715.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 = 0.00135 (206/152296) while in subpopulation NFE AF = 0.00221 (150/68018). AF 95% confidence interval is 0.00192. There are 1 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 206 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001441024.1. 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.4161_4166dupGCCATT	p.Leu1387_Pro1388dup	disruptive_inframe_insertion	Exon 25 of 26	NP_036441.2
SHANK2	NM_001441024.1		c.4281_4286dupGCCATT	p.Leu1427_Pro1428dup	disruptive_inframe_insertion	Exon 23 of 24	NP_001427953.1
SHANK2	NM_001441025.1		c.4110_4115dupGCCATT	p.Leu1370_Pro1371dup	disruptive_inframe_insertion	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.4161_4166dupGCCATT	p.Leu1387_Pro1388dup	disruptive_inframe_insertion	Exon 25 of 26	ENSP00000469689.2
SHANK2	ENST00000409161.5	TSL:1	c.2373_2378dupGCCATT	p.Leu791_Pro792dup	disruptive_inframe_insertion	Exon 9 of 10	ENSP00000386491.1
SHANK2	ENST00000916035.1		c.4110_4115dupGCCATT	p.Leu1370_Pro1371dup	disruptive_inframe_insertion	Exon 22 of 23	ENSP00000586094.1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00143

AC:

358

AN:

251174

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000781

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00238

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00164

AC:

2394

AN:

1461728

Hom.:

Cov.:

AF XY:

0.00158

AC XY:

1148

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00349

AC:

186

AN:

53300

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00189

AC:

2098

AN:

1111976

Other (OTH)

AF:

0.00123

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

152

303

455

606

758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<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:

0.00135

AC:

206

AN:

152296

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

105

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41574

American (AMR)

AF:

0.000523

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00221

AC:

150

AN:

68018

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.00214

Hom.:

Bravo

AF:

0.000952

EpiCase

AF:

0.00142

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Complex neurodevelopmental disorder (1)

not provided (1)

not specified (1)

SHANK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.8

Mutation Taster

=59/41

polymorphism

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over