NM_012309.5:c.1777+38048C>T

Variant names:

• chr11-70760395-G-A
• rs10899444
• NM_012309.5:c.1777+38048C>T

Variant summary

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

The NM_012309.5(SHANK2):​c.1777+38048C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 152,230 control chromosomes in the GnomAD database, including 49,797 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 0.80 (49797 hom., cov: 34)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.539
• Publications: 2 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.1777+38048C>T		intron_variant	Intron 14 of 25	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.1777+38048C>T		intron_variant	Intron 14 of 25	5	NM_012309.5	ENSP00000469689.2

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122304 AN: 152112 Hom.: 49763 Cov.: 34

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.828

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.882

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.904

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.796

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

GnomAD4 genome AF: 0.804 AC: 122395 AN: 152230 Hom.: 49797 Cov.: 34 AF XY: 0.803 AC XY: 59783 AN XY: 74412

African (AFR) AF: 0.677 AC: 28082 AN: 41506

American (AMR) AF: 0.827 AC: 12668 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.741 AC: 2572 AN: 3470

East Asian (EAS) AF: 0.882 AC: 4565 AN: 5176

South Asian (SAS) AF: 0.690 AC: 3320 AN: 4814

European-Finnish (FIN) AF: 0.904 AC: 9591 AN: 10610

Middle Eastern (MID) AF: 0.759 AC: 223 AN: 294

European-Non Finnish (NFE) AF: 0.865 AC: 58836 AN: 68022

Other (OTH) AF: 0.799 AC: 1691 AN: 2116

Alfa AF: 0.834 Hom.: 78263

Bravo AF: 0.796

Asia WGS AF: 0.785 AC: 2729 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.59
PhyloP100		-0.54
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: rs10899444; hg19: chr11-70606500;