11-70660101-G-T

Position:

• chr11-70660101-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012309.5(SHANK2):​c.1937-149C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 909,694 control chromosomes in the GnomAD database, including 97,983 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 0.40 (13498 hom., cov: 32)
  • Exomes 𝑓: 0.46 (84485 hom.)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00700

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.1937-149C>A		intron_variant		ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.1937-149C>A		intron_variant		5	NM_012309.5	ENSP00000469689	P1

Frequencies

GnomAD3 genomes AF: 0.402 AC: 60979 AN: 151842 Hom.: 13500 Cov.: 32

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.451

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.326

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.445

GnomAD4 exome AF: 0.460 AC: 348687 AN: 757730 Hom.: 84485 AF XY: 0.458 AC XY: 180843 AN XY: 395014

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.409

Gnomad4 ASJ exome AF: 0.409

Gnomad4 EAS exome AF: 0.310

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.406

Gnomad4 NFE exome AF: 0.508

Gnomad4 OTH exome AF: 0.449

GnomAD4 genome AF: 0.401 AC: 60985 AN: 151964 Hom.: 13498 Cov.: 32 AF XY: 0.395 AC XY: 29320 AN XY: 74252

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.403

Gnomad4 EAS AF: 0.326

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.449

Alfa AF: 0.365 Hom.: 1491

Bravo AF: 0.398

Asia WGS AF: 0.364 AC: 1267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.3
DANN	Benign	0.37

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

LitVar

Other links and lift over

dbSNP: rs525304; hg19: chr11-70506206; COSMIC: COSV53625241; COSMIC: COSV53625241;