NM_012309.5:c.4161_4166dupGCCATT

Variant names:

• chr11-70486126-G-GAATGGC
• rs756656381
• NM_012309.5:c.4161_4166dupGCCATT

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_012309.5(SHANK2):​c.4161_4166dupGCCATT​(p.Leu1387_Pro1388dup) 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_012309.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.81

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_012309.5.
• BP6: Variant 11-70486126-G-GAATGGC is Benign according to our data. Variant chr11-70486126-G-GAATGGC is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.4161_4166dupGCCATT	p.Leu1387_Pro1388dup	disruptive_inframe_insertion	Exon 25 of 26	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.4161_4166dupGCCATT	p.Leu1387_Pro1388dup	disruptive_inframe_insertion	Exon 25 of 26	5	NM_012309.5	ENSP00000469689.2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152178 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00143 AC: 358 AN: 251174 Hom.: 0 AF XY: 0.00144 AC XY: 196 AN XY: 135788

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 SAS 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.: 1 Cov.: 34 AF XY: 0.00158 AC XY: 1148 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00349

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74468

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00221

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.000952

EpiCase AF: 0.00142

EpiControl AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jun 02, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SHANK2: PM4, BS1 -

SHANK2-related disorder Benign:1

May 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756656381; hg19: chr11-70332231;