NM_012309.5:c.1854-1994G>A

Variant names:

• chr11-70663672-C-T
• rs471931
• NM_012309.5:c.1854-1994G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012309.5(SHANK2):​c.1854-1994G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 151,968 control chromosomes in the GnomAD database, including 14,821 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 0.42 (14821 hom., cov: 32)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.96
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.1854-1994G>A		intron_variant	Intron 15 of 25	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.1854-1994G>A		intron_variant	Intron 15 of 25	5	NM_012309.5	ENSP00000469689.2

Frequencies

GnomAD3 genomes AF: 0.421 AC: 64002 AN: 151848 Hom.: 14822 Cov.: 32

Gnomad AFR AF: 0.228

Gnomad AMI AF: 0.608

Gnomad AMR AF: 0.462

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.471

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.421 AC: 64017 AN: 151968 Hom.: 14821 Cov.: 32 AF XY: 0.415 AC XY: 30797 AN XY: 74268

African (AFR) AF: 0.228 AC: 9462 AN: 41486

American (AMR) AF: 0.461 AC: 7038 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1472 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1654 AN: 5142

South Asian (SAS) AF: 0.359 AC: 1727 AN: 4806

European-Finnish (FIN) AF: 0.414 AC: 4378 AN: 10580

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36616 AN: 67900

Other (OTH) AF: 0.474 AC: 1001 AN: 2112

Alfa AF: 0.496 Hom.: 11379

Bravo AF: 0.418

Asia WGS AF: 0.369 AC: 1284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	9.7
DANN	Benign	0.59
PhyloP100		2.0
Mutation Taster		=100/0	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: rs471931; hg19: chr11-70509777;