11-71118812-T-C

Position:

• chr11-71118812-T-C

Variant summary

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

The NM_012309.5(SHANK2):​c.411+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 1,531,148 control chromosomes in the GnomAD database, including 192,460 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 0.49 (18712 hom., cov: 33)
  • Exomes 𝑓: 0.50 (173748 hom.)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.83

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=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.411+17A>G		intron_variant		ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.411+17A>G		intron_variant		5	NM_012309.5	ENSP00000469689	P1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75100 AN: 151964 Hom.: 18682 Cov.: 33

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.456

GnomAD3 exomes AF: 0.501 AC: 69466 AN: 138556 Hom.: 17824 AF XY: 0.493 AC XY: 35622 AN XY: 72274

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.412

Gnomad EAS exome AF: 0.600

Gnomad SAS exome AF: 0.426

Gnomad FIN exome AF: 0.523

Gnomad NFE exome AF: 0.491

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.500 AC: 689248 AN: 1379066 Hom.: 173748 Cov.: 32 AF XY: 0.496 AC XY: 335984 AN XY: 677428

Gnomad4 AFR exome AF: 0.482

Gnomad4 AMR exome AF: 0.556

Gnomad4 ASJ exome AF: 0.418

Gnomad4 EAS exome AF: 0.637

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.527

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.495

GnomAD4 genome AF: 0.494 AC: 75194 AN: 152082 Hom.: 18712 Cov.: 33 AF XY: 0.497 AC XY: 36946 AN XY: 74348

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.534

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.601

Gnomad4 SAS AF: 0.422

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.460

Alfa AF: 0.501 Hom.: 4646

Bravo AF: 0.495

Asia WGS AF: 0.508 AC: 1767 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.93
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3924047; hg19: chr11-70829858;