NM_012309.5:c.1937-149C>A

Variant names:

• chr11-70660101-G-T
• rs525304
• NM_012309.5:c.1937-149C>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.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
• Publications: 8 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012309.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	NM_012309.5	MANE Select	c.1937-149C>A		intron	N/A	NP_036441.2
	SHANK2	NM_001441024.1		c.2108-149C>A		intron	N/A	NP_001427953.1
	SHANK2	NM_001441025.1		c.1937-149C>A		intron	N/A	NP_001427954.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHANK2	ENST00000601538.6	TSL:5 MANE Select	c.1937-149C>A		intron	N/A	ENSP00000469689.2
	SHANK2	ENST00000409161.5	TSL:1	c.170-149C>A		intron	N/A	ENSP00000386491.1
	SHANK2	ENST00000449116.6	TSL:1	n.246-149C>A		intron	N/A

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

African (AFR) AF: 0.194 AC: 3893 AN: 20036

American (AMR) AF: 0.409 AC: 14028 AN: 34336

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 8201 AN: 20042

East Asian (EAS) AF: 0.310 AC: 10237 AN: 33020

South Asian (SAS) AF: 0.329 AC: 21054 AN: 64024

European-Finnish (FIN) AF: 0.406 AC: 16025 AN: 39436

Middle Eastern (MID) AF: 0.390 AC: 1169 AN: 2996

European-Non Finnish (NFE) AF: 0.508 AC: 257498 AN: 506944

Other (OTH) AF: 0.449 AC: 16582 AN: 36896

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

African (AFR) AF: 0.209 AC: 8676 AN: 41452

American (AMR) AF: 0.445 AC: 6792 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1396 AN: 3464

East Asian (EAS) AF: 0.326 AC: 1678 AN: 5148

South Asian (SAS) AF: 0.335 AC: 1610 AN: 4806

European-Finnish (FIN) AF: 0.400 AC: 4215 AN: 10548

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.517 AC: 35157 AN: 67964

Other (OTH) AF: 0.449 AC: 947 AN: 2110

Alfa AF: 0.458 Hom.: 24423

Bravo AF: 0.398

Asia WGS AF: 0.364 AC: 1267 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.3
DANN	Benign	0.37
PhyloP100		0.0070
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: rs525304; hg19: chr11-70506206; COSMIC: COSV53625241; COSMIC: COSV53625241;