chr11-70820660-C-T

Variant names:

• chr11-70820660-C-T
• rs11237599
• NM_012309.5:c.1197G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001441024.1(SHANK2):​c.1368G>A​(p.Ala456Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 696,650 control chromosomes in the GnomAD database, including 12,270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2328 hom., cov: 33)
  • Exomes 𝑓: 0.18 (9942 hom.)
• Consequence: SHANK2 NM_001441024.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -0.373
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 11-70820660-C-T is Benign according to our data. Variant chr11-70820660-C-T is described in ClinVar as Benign. ClinVar VariationId is 437876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.373 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	NM_012309.5	MANE Select	c.1197G>A	p.Ala399Ala	synonymous	Exon 12 of 26	NP_036441.2
	SHANK2	NM_001441024.1		c.1368G>A	p.Ala456Ala	synonymous	Exon 13 of 24	NP_001427953.1
	SHANK2	NM_001441025.1		c.1197G>A	p.Ala399Ala	synonymous	Exon 12 of 23	NP_001427954.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.1197G>A	p.Ala399Ala	synonymous	Exon 12 of 26	ENSP00000469689.2
	SHANK2	ENST00000916035.1		c.1197G>A	p.Ala399Ala	synonymous	Exon 12 of 23	ENSP00000586094.1
	SHANK2	ENST00000916037.1		c.1197G>A	p.Ala399Ala	synonymous	Exon 12 of 23	ENSP00000586096.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23143 AN: 152058 Hom.: 2327 Cov.: 33

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.0776

Gnomad SAS AF: 0.0473

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.170 AC: 22433 AN: 131582 AF XY: 0.163

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.237

Gnomad ASJ exome AF: 0.144

Gnomad EAS exome AF: 0.0781

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.178 AC: 96698 AN: 544474 Hom.: 9942 Cov.: 0 AF XY: 0.171 AC XY: 49866 AN XY: 292360

African (AFR) AF: 0.0400 AC: 608 AN: 15186

American (AMR) AF: 0.229 AC: 7547 AN: 32966

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 2545 AN: 18832

East Asian (EAS) AF: 0.0634 AC: 2014 AN: 31760

South Asian (SAS) AF: 0.0495 AC: 2986 AN: 60298

European-Finnish (FIN) AF: 0.220 AC: 9936 AN: 45202

Middle Eastern (MID) AF: 0.104 AC: 413 AN: 3984

European-Non Finnish (NFE) AF: 0.214 AC: 65614 AN: 306506

Other (OTH) AF: 0.169 AC: 5035 AN: 29740

GnomAD4 genome AF: 0.152 AC: 23142 AN: 152176 Hom.: 2328 Cov.: 33 AF XY: 0.150 AC XY: 11162 AN XY: 74374

African (AFR) AF: 0.0405 AC: 1683 AN: 41566

American (AMR) AF: 0.192 AC: 2944 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.129 AC: 447 AN: 3468

East Asian (EAS) AF: 0.0778 AC: 401 AN: 5154

South Asian (SAS) AF: 0.0471 AC: 227 AN: 4820

European-Finnish (FIN) AF: 0.222 AC: 2352 AN: 10602

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14532 AN: 67952

Other (OTH) AF: 0.155 AC: 328 AN: 2114

Alfa AF: 0.190 Hom.: 4891

Bravo AF: 0.149

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Autism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.4
DANN	Benign	0.96
PhyloP100		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11237599; hg19: chr11-70666765;