11-71165389-T-C

Variant names:

• chr11-71165389-T-C
• rs7124728
• NM_012309.5:c.-12-18051A>G

Variant summary

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

The NM_012309.5(SHANK2):​c.-12-18051A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 152,068 control chromosomes in the GnomAD database, including 31,662 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 0.63 (31662 hom., cov: 32)
• Consequence: SHANK2 NM_012309.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.24
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHANK2	NM_012309.5	c.-12-18051A>G		intron_variant	Intron 2 of 25	ENST00000601538.6	NP_036441.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHANK2	ENST00000601538.6	c.-12-18051A>G		intron_variant	Intron 2 of 25	5	NM_012309.5	ENSP00000469689.2

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96110 AN: 151950 Hom.: 31623 Cov.: 32

Gnomad AFR AF: 0.808

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.737

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.595

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

GnomAD4 genome AF: 0.633 AC: 96203 AN: 152068 Hom.: 31662 Cov.: 32 AF XY: 0.634 AC XY: 47119 AN XY: 74320

African (AFR) AF: 0.808 AC: 33500 AN: 41472

American (AMR) AF: 0.461 AC: 7037 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1694 AN: 3464

East Asian (EAS) AF: 0.516 AC: 2660 AN: 5152

South Asian (SAS) AF: 0.738 AC: 3550 AN: 4810

European-Finnish (FIN) AF: 0.666 AC: 7059 AN: 10602

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38727 AN: 67970

Other (OTH) AF: 0.596 AC: 1259 AN: 2112

Alfa AF: 0.609 Hom.: 10743

Bravo AF: 0.618

Asia WGS AF: 0.639 AC: 2222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.057
DANN	Benign	0.23
PhyloP100		-3.2

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: rs7124728; hg19: chr11-70876435;